2674 Current Medicinal Chemistry, 2011, 18, 2674-2685

Present and Future of PI3K Pathway Inhibition in Cancer: Perspectives and

Limitations
E. Ciraolo#, F. Morello# and E. Hirsch*

Department of Genetics, Biology and Biochemistry, Molecular Biotecnology Center, University of Torino, Torino, Italy
Abstract: Phosphoinositide 3-kinases (PI3Ks) control key signaling pathways in cancer cells, leading to cell proliferation, survival,
motility and angiogenesis. In several human cancers, activation of PI3Ks results from gain-of-function or over-expression of PI3Ks
and/or hyperactivity of up- or downstream players in the pathway. As inhibition of PI3Ks and downstream targets such as mammalian
target of rapamycin (mTOR) has been shown to reduce tumor growth in vitro and in preclinical models, several small molecule inhibitors
of PI3Ks are currently undergoing clinical trial as novel agents in cancer therapy. These drugs include inhibitors targeting all class I
PI3Ks (
, , ,  isoforms), compounds blocking selective PI3K isoforms and dual inhibitors active on both PI3Ks and mTOR. Herein,
we summarize the pharmacology and preliminary clinical data of the main PI3K inhibitors undergoing clinical trial. We will also review
the preclinical studies documenting the major effects of systemic PI3K inhibition on non-cancer tissues, which have shed light on
potential side effects, caveats and limitations for PI3K blockade in patients.
Keywords: PI3K, mTOR, Akt, cancer, enzyme inhibitors.

1. INTRODUCTION the PtdIns(3,4,5)P3 signals, and PI-5Pase as INPP5E and SKIP,

which hydrolyze a broader range of 5-phosphoinositides [5]. Unlike
Phosphoinositide 3-kinases (PI3Ks) constitute a family of PTEN, PI-5Pases function as more complex modulators of
enzymes widely involved in cell signaling and controlling a broad PtdIns(3,4,5)P3 signaling, as their PtdIns(3,4)P2 product can still
number of cellular processes including cell proliferation, survival, function as a signaling molecule by recruiting and activating Akt [6, 7].
motility and metabolism. Upon membrane receptor activation,
PI3Ks catalyze the D3-phosphorylation of phosphatidylinositol, Major effectors of PI3Ks are the serine-threonine kinase protein
thus generating an array of lipid second messengers mediating kinase B/Akt and the phosphoinositide-dependent kinase-1 (PDK1).
signal transduction. Based on structural and functional properties, Targets of Akt which mediate important biological effects of the
PI3Ks can be grouped into three different classes. Class I, the best PI3K pathway include transcription factors (e.g. FOXOs) and other
known PI3Ks, selectively phosphorylate phosphatydilinositol(4,5)P2 kinases, such as the mammalian target of rapamycin (mTOR) and
(PtdIns(4,5)P2/PIP2) to phosphatydilinositol(3,4,5)P3 (PtdIns(3,4,5) ribosomal p70 S6 kinase (S6K1) (Fig. 1). mTOR can be part of two
P3/PIP3). They are heterodimers composed of a catalytic subunit distinct protein complexes named mTOR complex 1 (TORC1) and
and a regulatory/adaptor subunit. All p110 catalytic subunits 2 (TORC2) [8]. TORC1 is constituted by mTOR, the regulatory
(p110
, ,  and ) share substantial homology, while different associated protein of mTOR (Raptor), mammalian LST8/G-protein
regulatory subunits exist. PI3K
,  and  (constituting class IA) are -subunit like protein (mLST8/GL), PRAS40 and DEPTOR. Akt
composed of a p110 catalytic and a p85 regulatory subunit, while positively controls TORC1 by a dual mechanism of sequential
PI3K (unique member of class IB) possesses a p110 and a p101 inactivations: (i) phosphorylation and inactivation of PRAS40, a
or p84/87 regulatory subunit. PI3K
and PI3K are ubiquitously negative regulator of mTOR, and (ii) phosphorylation and
expressed. Instead, expression of PI3K and PI3K is mostly inactivation of the tuberous sclerosis (TSC2/TSC1) complex, a
restricted to spleen, leukocytes and thymus [1]. GTPase-activating protein which activates the small GTPase Rheb.
Once triggered by Akt, TORC1 phosphorylates its key target S6K1,
Class IA PI3Ks are recruited and activated by tyrosine kinase which functions as a regulator of ribosomal protein translation and
receptors (RTKs, such as growth factor and insulin receptors) biogenesis. While TORC1 operates downstream Akt, the TORC2
through binding of the p85 regulatory subunit to tyrosine- complex, formed by mTOR and the rapamycin-insensitive
phosphorylated motifs [2]. Conversely, G-protein coupled receptors companion of mTOR (RICTOR), mediates the phosphorylation of
(GPCRs) can only activate PI3K and PI3K through the G Akt on Ser-473 upon cell stimulation with growth factors. Together
subunit of G-proteins [3]. Another source of PI3K activation is with the PDK1-mediated phosphorylation in the activation loop
represented by small monomeric GTPase Rat Sarcoma (Ras). (Thr-308), phosphorylation of Akt by mTORC2 is necessary for the
Engagement of PI3Ks leads to the local accumulation of PIP3, full activation of Akt [9].
which triggers further signaling by acting as a docking site for
effector proteins containing a pleckstrin homology (PH)-domain, 2. HYPERACTIVATION OF THE PI3K SIGNALING IN
which translocate to the plasma membrane. As downstream signal CANCER
proceeds, the PI3K pathway is interrupted by the action of
phosphatases which degrade PtdIns(3,4,5)P3 to PtdIns(4,5)P2. The The PI3K signaling pathway is frequently altered in human
best characterized phosphatase counterbalancing PI3K action is cancers as a result of (i) activating mutations of one PI3K and/or
represented by the phosphatase and tensin homolog (PTEN). On the (ii) alterations upstream (e.g. RTKs) or downstream of PI3Ks (e.g.
other hand, PtdIns(3,4,5)P3 is also rapidly degraded by specific Akt and PTEN), which promote cell proliferation, resistance to
inositol polyphosphate 5-phosphatases (PI-5Pase) to PtdIns(3,4)P2, apoptosis, anabolism, invasiveness and angiogenesis. The gene
which is in turn dephosphorylated by inositol polyphosphate 4- encoding for p110
(PIK3CA) is one of the most frequently
phosphatase (4-ptase) to form PtdIns(3)P [4]. In mammals, the PI- mutated oncogenes in human tumors [10]. Indeed, the frequent
5Pases are a large family of phosphatases composed by ten occurrence of gain-of-function cancer-specific mutations in
different enzymes such as the SH2-domain-containing inositol PIK3CA makes of p110
an ideal therapeutic target. Somatic
phosphatase 1 (SHIP1) and SHIP2, which predominantly modulate mutations of the PIK3CA gene have been reported in several
cancer types including colon, ovary, breast, brain, liver, stomach,
*Address correspondence to these authors at the Department of Genetics, Biology and endometrial and lung cancer [11]. Three hot-spot mutations
Biochemistry, Molecular Biotecnology Center, University of Torino, Torino, Italy; Tel: (E542K, E545K and H1047R) represent 80% of all PIK3CA
+39 0116706425; Fax: +39 0116706432; E-mail: [email protected] mutations found in tumors. They map two distinct domains of the
#
These authors equally contributed to the manuscript. p110
protein, indicating that different molecular mechanisms can
0929-8673/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.
PI3K Inhibitors in Cancer Current Medicinal Chemistry, 2011 Vol. 18, No. 18 2675

Growth Factors
Insulin

P P
IRS
P P
?
PI3K mTOR
TORC2
RICTOR

P
Akt
P

mTOR
TORC1
RAPTOR

P
S6K1

Fig. (1). Schematic representation of the PI3K-Akt-mTOR signaling pathway and feedback loop. Growth factors such as insulin bind to the extracellular
portion of their RTKs. Once activated by autophosphorylation RTKs recruit IRS proteins, which bind the regulatory subunit of class I PI3Ks. In turn, activated
PI3Ks engage downstream proteins such as Akt, which regulates the activation of mTOR. mTOR forms the TORC1 complex with RAPTOR, which directly or
indirectly controls ribosomal p70 S6 kinase (S6K1), a regulator of ribosomal protein translation and biogenesis. S6K1 mediates a negative feedback on IRS by
phosphorylating it. A distinct mTOR complex (TORC2), composed by mTOR and RICTOR, is involved in the signaling pathway downstream RTKs. Although
the mechanism of TORC2 activation is unknown, TORC2 triggers the activity of Akt through direct phosphorylation.

PIK3CA RAS PI3K inhibition:

(H1047R, E542K, E545K)
GDC-0941
XL147
PX-866
PI3Ka NVP-BKM120

RTKs Cell proliferation

P
P
P Reduced apoptosis
P P

PtdIns(4,5)P2 PtdIns(3,4,5)P3 Tumorigenesis

PI3Kb PTEN

Fig. (2). PI3K deregulation in cancer. Accumulation of PIP3 amplifies intracellular signals leading to proliferation, survival and ultimately tumorigenesis.
Causes of PIP3 elevation include: gain-of-function mutations in the gene encoding for PI3K
, mutated Ras and RTKs and loss-of-function mutations of the
phosphatase PTEN. The latter conditions activate both PI3K
and PI3K.

sustain the gain of function of p110
[12]. E542K and E545K It is still unclear if PIK3CA mutations actually participate in the
mutations localize within the helical domain, while H1047R lies initiation of tumorigenesis or if they are merely needed to sustain
within the kinase domain. Mutations in the helical domain seem to cell growth in advanced tumors. When expressed in chicken
alter the binding of p110
to the regulatory subunit p85 and may embryo fibroblasts, E542K, E545K and H1047R p110
mutants are
interfere with the inhibitory action of p85 on p110
, thus able to induce oncogenic transformation with high efficiency and
mimicking an activation state by RTKs. H1047 is the most frequent this transforming ability correlates with an elevated lipid kinase
mutation and occurs at the end of the activation loop of p110
, activity of each mutant [14]. In addition, the expression of PIK3CA
where it appears to directly influence the interaction between p110
mutants in vitro results in a constitutive activation of Akt even in
and PIP2 [13]. the absence of growth factors, thus producing resistance to
2676 Current Medicinal Chemistry, 2011 Vol. 18, No. 18 Ciraolo et al.

apoptosis, increased cell migration and invasion. Nonetheless, the leukemia [32], in the human Jurkat T cell line derived from a
impact of PIK3CA mutation on the PI3K signaling pathway in vivo patient with acute lymphoblastic leukaemia and in adult T cell
is variable and does not always correlate with Akt activation [15, leukaemia or lymphoma [33, 34]. Conversely, SHIP2 has emerged
16]. Importantly, gain-of-function mutations in PIK3CA genes as a positive regulator in breast cancer, since it is increased in a
often coexist with additional alterations in the PI3K pathway in panel of breast cancer cell lines and its depletion in the MDA-231
several types of tumors. For instance, mutated p110
has been breast cancer cells results in decreased cell proliferation and tumor
associated with PTEN and K-Ras mutations [17, 18] or with formation in nude mice [35]. Other PI-5Ps show changes in their
ERBB2/HER2 overexpression [19, 20]. Co-occurrence of p110
expression levels in different cancer types. For instance, INPP5E
gain-of-function with other specific oncogenic alterations in the shows increased expression in samples from patients with non-
PI3K pathway suggests that the mutational status of p110
and Hodgkin’s lymphoma following treatment [36], uterine
p85
may have different consequences on tumor formation and leiomyosarcoma samples [37] and in gemcitabine-resistant
progression depending on tissue specificity and cell type. Of pancreatic cancer cell lines [38]. On the contrary, INPP5E
interest, it has been shown that PIK3CA mutations contribute to expression is downregulated in stomach cancer and metastatic
tumorigenicity not only through Akt, but also via Akt-independent adenocarcinomas [39, 40].
mechanisms. For instance, alternative tumorigenic signaling has Somatic mutations have been reported in the regulatory subunit
been shown to stem from PDK1 and SGK3 in PIK3CA mutant p85
(PIK3R1 gene), although their prevalence is lower compared
cancer cells [16]. to mutations of p110
. Instead, mutations in other PI3K regulatory
To date, no genetic alterations have been found in the genes subunits (encoding p85, PIK3R2, and p55
, PIK3R3), are low or
encoding for p110,
and . Conversely, increased expression of absent, thus suggesting an isoform-specific role for p85
in cancer.
p110 and p110 occurs in glioblastomas [21] colon and bladder Most p85
mutations (i.e. D560Y, N564D, QYL579 deletion,
tumors [22]. Indeed, overexpression of wild-type p110,  and
is DS459delN and DKRMNS560del) cluster in the two SH2 domains
sufficient to induce an oncogenic phenotype in cultured cells [23]. and in the inter-SH2 domain [41, 42] and were identified primarily
Moreover, expression of myristoylated p110 induces the in glioblastoma [43]. Analysis of this region has revealed that these
development of prostatic intraepithelial neoplasias in mice [24] and mutants, even if they retain the ability to bind the p110 catalytic
similarly, expression of myristoylated p110
can induce a subunit, lose their inhibitory activity on p110. In addition, p85

constitutive activation of Akt in Rat1 fibroblasts [25]. p110
has mutations should be able to activate indifferently all class IA
also been found overexpressed in pancreatic cancer, where it is isoforms. Since p110 and p110 have been found over-expressed
required for cell proliferation, as shown by reduced cell growth in in certain human cancers, the co-expression of mutated p85
in
the lack of p110
lipid kinase activity [26]. Taken together, these such tumors may further enhance the activity of these non-mutated
findings suggest that p110,
and  explicate their oncogenic catalytic subunits. However, a recent report has shown that, at least
potential as wild-type proteins. Recently, p110 has emerged as an in glioblastoma, p110
is necessary and sufficient in mediating
interesting target in certain tumor types such as breast and prostate oncogenic transformation induced by p85 mutants. While ablation
cancers [27, 28]. In a mouse model of breast cancer driven by of the p110
kinase activity through a selective inhibitor reduces by
hyperactivation of the HER2 signaling pathway, the absence of 75-80% the in vitro focus formation induced by the p85 mutants,
p110 lipid kinase activity strongly delays the appearance of the inhibition of p110, p110
or p110 has no effect [44].
first tumor and reduces tumor growth in vitro even in a context of
PTEN down-regulation [29]. Similarly, ablation of p110 blocks 3. PI3K INHIBITORS
PTEN loss-driven tumorigenesis in the prostate. In this model,
PTEN-mediated transformation appears to strictly depend on Growing knowledge of the molecular bases of cancer has
p110, since prostate-specific knockout of p110
fails to affect shifted the interest of current drug discovery towards molecularly-
tumor formation [30]. These observations demonstrate the existence targeted therapies implying high molecular selectivity, high tumor
of a link between PTEN loss and p110 signaling. As a matter of specificity and low general toxicity. In the last years, discovery of
fact, cancer cells harboring PTEN-null alleles, in the absence of the oncogenic activity of PI3Ks has encouraged many companies
p110
mutations, depend on p110 lipid kinase activity, since and academic laboratories to initiate a variety of strategies to inhibit
treatment with p110-selective inhibitors can block cell growth the PI3K pathway at different points (summarized in Table 1).
[31]. Several PI3K inhibitors have so far been developed and are now
Since the PIP3 signaling is additionally regulated by PI-5Pases, being evaluated in preclinical and early clinical studies. Similar to
also the tumorigenic potential of these phosphatases has been traditional tyrosine kinase inhibitors, all available class I PI3K
largely investigated. SHIP1 levels are reduced in chronic myeloid inhibitors are small molecules that bind competitively and in

Table 1. IC50 Values and Preclinical Anti-Tumor Activity of the Main PI3K Inhibitors

Compound IC50 (nM) IC50 (nM) IC50 (nM) IC50 (nM) Preclinical anti-tumor activity
PI3K
PI3K PI3K PI3K

GDC-0941 3 33 75 3 breast, glioblastoma, lung, prostate [48, 50, 138-141]

(Genentech/ Piramed)
XL-147 (Exelixis) 39 383 23 36 breast, lung, ovary, prostate, glioma [55]
PX-866 5.5 >300 9 2.7 colon, glioblastoma, lung, ovary, pancreas, prostate [56-58, 78,
(Oncothyreon) 142]
NVP-BKM120 35 medulloblastoma [143]
(Novartis)
CAL-101 (Calistoga 820 565 89 2.5 acute myeloid leukemia, chronic lymphatic leukemia, multiple
Pharmaceuticals) myeloma, non-Hodgkin’s lymphoma [65, 66, 144]
NVP-BEZ235 4 75 5 7 glioblastoma, lung, multiple myeloma, non-Hodgkin’s
(Novartis) lymphoma, pancreas, prostate, sarcoma [74-76, 88, 145-147]
PI3K Inhibitors in Cancer Current Medicinal Chemistry, 2011 Vol. 18, No. 18 2677

Table 2. Summary of the Side Effects of PI3K Inhibitors Observed so Far in Limited Cohorts of Human Patients.

Target Drug Side effects Serious adverse events Clinical studies

class I PI3Ks
PX-866 (Oncothyreon) abdominal discomfort, diarrhea [59] Phase I, Phase II
(solid tumors)
XL147 (Exelixis) transaminase elevation, hyperglicemia skin rash, arterial thrombosis Phase I, Phase II
[55] [55] (solid tumors, lymphomas)
NVP-BKM120 (Novartis) Phase I, Phase II
(solid tumors)
GDC-0941 (Genentech/ Piramed) nausea, fatigue, diarrhea, peripheral Phase I
edema, dysgeusia [45] (solid tumors)
PI3K

CAL-101 (Calistoga Pharmaceuticals) Phase I, Phase II
(lymphomas, leukemias)
class I PI3Ks, mTOR
NVP-BEZ235 (Novartis) Phase I, Phase II
(solid tumors)
SF1126 (Semafore Pharmaceutics) nausea/vomiting, fatigue [148] transaminase elevation [149] Phase I
(solid tumors)
XL765 (Exelixis) transaminase elevation, nausea, Phase I, Phase II
diarrhea, rash, increase in plasma (solid tumors)
insulin [77]
GSK2126458 Phase I
(Glaxo) (solid tumors)
GDC-0980 Phase I
(Genentech/ Piramed) (solid tumors, lymphomas)

general reversibly the ATP-binding site of the catalytic domain. A In addition, several reports have shown that treatment with GDC-
first set of PI3K inhibitors has now entered in phase I and II clinical 0941 is beneficial in combination with other chemotherapeutic
trials (summarized in Table 2). These compounds include pan-PI3K agents such as trastuzumab, pertuzumad and docetaxel [50].
inhibitors and isoform-specific inhibitors. Moreover, the combination of GDC-0941 with a B-Raf inhibitor is
beneficial in cancer models with oncogenic B-Raf and PTEN
3.1. Pan-PI3K Inhibitors deficiency [51].

New generation pan-PI3K inhibitors (GDC-0941, XL147, XL147

PX866, NVP-BKM120) target all class I PI3Ks and exhibit a potent XL147 is a small molecule inhibitor active against all class I
antiproliferative activity against a broad panel of tumor cell lines. PI3Ks (IC50 = 39, 383, 23 and 36 nM for p110
, ,
and ) and
Although the published literature about these inhibitors is still inactive on VPS34, DNA-PK and mTOR [52]. XL147 inhibits
limited, initial results about their efficacy on tumor growth in PI3K signaling in tumor cell lines in vitro and induces reduction of
preclinical and phase I and II clinical trials are becoming available. tumor growth or shrinkage in preclinical models of breast, lung,
GDC-0941 ovarian, prostate, and glioma tumors in vivo [53, 54]. XL147 has
now entered phase I/II clinical trials, which will evaluate the
GDC-0941 is a potent, selective and orally bioavailable pan- pharmacokinetics of XL147 as well as its safety and clinical effect
inhibitor of PI3Ks currently evaluated in several phase I clinical in several tumors such as solid tumors, lymphomas, metastatic
trials (http://ClinicalTrials.gov, [45]) on patients with advanced breast cancers and endometrial cancers, alone or in combination
solid tumors such as HER2 positive metastatic breast cancer and with other chemotherapeutic agents (http://ClinicalTrials.gov, [55]).
advanced non-small cell lung cancer. GDC-0941 is substantially
equipotent against all members of class I PI3Ks, with an IC50 of PX-866
0.003, 0.033, 0.075 and 0.003 μM against the p110
, p110, p110 PX-866 is a semisynthetic viridian possessing a potent and
and p110 respectively [46, 47]. Several studies have documented selective inhibitory action against all class I PI3Ks, with a higher
the effects of GDC-0941 on tumor growth both in vitro and in vivo. selectivity versus p110
and p110 (IC50 = 5.5 nM, >300 nM, 9 nM
This pro-drug can inhibit proliferation in several tumor cell lines at and 2.7 nM for p110
, p110, p110
, p110 respectively) [56]. PX-
the submicromolar range, including glioblastoma, breast and 866 is metabolized to N-deallylated and N-di-deallylated
prostate lines carrying genetic aberrations in the PI3K pathway. metabolites which retain an inhibitory activity on PI3Ks at low
Moreover, inhibition of PI3K by GDC-0941 is often associated nanomolar concentrations. Compared to other PI3K inhibitors, PX-
with a reduction in Akt (Ser473) phosphorylation [48]. The efficacy 866 and its metabolites are irreversible inhibitors of PI3K, so that
of GDC-0941 has also been demonstrated in mouse tumor the level of PI3K inhibition may directly correlate to the plasma
xenograft models and in two transgenic mouse models of HER2 concentrations of the drug. In xenograft mouse models, PX-866
dependent inducible lung cancer (ERBB2YVMA and LTM) [49]. exhibits antitumor activity against different tumors such as ovarian
Treatment with GDC-0941 150 mg/kg leads to pronounced tumor cancer and glioblastoma, alone or in combination with others agents
shrinkage in ERBB2YVMA, whereas in LTM mice GDC-0941 and radiation [57]. Moreover, PX-866 inhibits cancer cell motility
induces inhibition of tumor growth compatible with stable disease. at subnanomolar concentrations and in some cases (e.g.
2678 Current Medicinal Chemistry, 2011 Vol. 18, No. 18 Ciraolo et al.

glioblastoma), increases autophagy, and reduces tumor invasiveness LY294002 and allows the drug to localize in the neovascular
and angiogenesis [58, 90]. Taken together, these data indicate PX- component of growing tumors through its binding to specific
866 as a clinically promising agent. PX-866 is currently under integrins. Indeed, LY294002 alone is poorly soluble and has a short
evaluation in a phase I clinical trial for the treatment of advanced half-life, which limits its use in clinical pharmacology. On the
solid tumors [59]. contrary, SF1126 is highly water-soluble, has favorable
NVP-BKM120 pharmacokinetics and is converted to LY29400 selectively within
the tumor tissue [71]. Thus, its antitumor activity mostly relies on
Limited data are available about NVP-BKM120, as no its pharmacokinetic accumulation. SF1126 shows a potent
published information about its selectivity, potency, antitumor activity against multiple human tumor types in vivo, is
pharmacodinamics and pharmacokinetics are presently available. well tolerated in mouse, rat and canine models, is potently
This compound was presented at the 101st American Association antiangiogenic and augments the antitumor activity of taxotere in a
for Cancer (2010), where it was described as a potent and highly prostate cancer xenograft model. In addition, SF1126 inhibits
specific oral pan-class I PI3K inhibitor. In addition, it should not proliferation, and induces G1 arrest and apoptosis of SKBR3,
exhibit activity against mTOR and Vps34. NVP-BKM120 is under BT474 cell lines and trastuzumab-resistant HER2 overexpressing
evaluation in 3 different phase I/II clinical trials on advanced solid cells [72]. A clinical trial of SF1126 on patients with solid tumors is
tumors and HER2 overexpressing breast cancers insensitive to currently ongoing [73].
trastuzumab (http://ClinicalTrials.gov, [60]).
NVP-BEZ235
3.2. Selective PI3K Inhibitors The imidazoquinazoline NVP-BEZ235 inhibits both PI3K and
Compared to pan-PI3K inhibitors, isoform-specific inhibitors mTOR kinase activity with IC50 values of 4 nM (p110
), 75 nM
have the potential to retain their therapeutic effect while limiting (p110), 7 nM (p110) and 5 nM (p110
) and 20.7 nM for mTOR.
adverse effects and thus increasing tolerability. Disclosure of the This molecule can effectively and specifically block hyperactivated
crystal structure of p110
[61], p110
[62] and p110 [63] has PI3K signaling by inducing G1 cell cycle arrest. Moreover, the
recently allowed to uncover the structural determinants that govern compound is well tolerated and leads to inhibition of tumor growth
the selectivity of PI3K inhibitors. Importantly, these findings are compatible with stable disease in human cancers. In addition, NVP-
highly useful for the synthesis of highly selective and potent BEZ235 reverses the hyperactivation of the PI3K/mTOR pathway
inhibitors against different p110 isoforms. Future design efforts will caused by the oncogenic mutations of p110
(E545K and H1047R)
further benefit from the availability of structure, not yet disclosed, [74]. NVP-BEZ235 has also been evaluated in combination with
of p110 and of phosphatidylinositol-3 kinase related kinases conventional cytotoxic agents, showing promising efficacy with
(PIKKs) such as mTOR, ATM and ATR. either doxorubicin or vincristine [75]. This molecule is under
evaluation in phase I/II clinical trials in patients with advanced
CAL-101 is the unique selective PI3K inhibitor investigated in solid malignancies and advanced breast cancer
preclinical studies. Recently, CAL-101 has entered phase I and II (http://ClinicalTrials.gov, [76]).
clinical trial (http://ClinicalTrials.gov, [64]). This compound shows
a 40-300-fold selectivity for p110 compared to other PI3K Other molecules defined as dual PI3K/mTOR inhibitors include
isoforms and exhibits a broad preclinical anti-tumor activity against GSK2126458, XL765 [77] and GDC-0980. Also these compounds
a range of hematologic malignancies such as relapsed or refractory are currently evaluated in preclinical and clinical studies in
chronic lymphatic leukemia (CLL), indolent non-Hodgkin’s advanced solid tumors and lymphomas.
lymphoma (NHL), aggressive NHL, acute myeloid leukemia
(AML) and multiple myeloma (MM) [65, 66]. 3.3. PI3K Inhibitors in Combination Therapies
Dual PI3K/mTOR Inhibitors All available PI3K inhibitors represent an optimal tool to block
mTOR is a critical node for the control of the cell growth and cancer cell proliferation, but they appear poorly cytotoxic. Clear
metabolism and has been widely implicated in signals mediating cytotoxic effects have been demonstrated only for the dual
cancer survival. mTOR exists in two complexes, mTORC1 and the PI3K/mTOR inhibitors SF1126 and NVP-BEZ235. On these bases,
mTORC2. mTORC1 is a master regulator of cell size which is in recent studies have shown that combination of PI3K inhibitors with
part regulated by growth factors signaling through the RTK-PI3K- other cytotoxic agents or radiation can increase to a great extent the
Akt axis as well as by nutrients, hypoxia or AMP signaling cytotoxic response of different tumors [78, 79]. This may help
(reviewed in [8]). mTORC1 is also involved in a negative feedback improve therapeutic responses by boosting tumor regression and
loop that inhibits IRS-1 protein, thus inhibiting Akt and switching preventing subsequent relapse. As activation of the PI3K/Akt
off the RTK signaling pathway [67, 68]. On the other hand, pathway in treated tumors plays a pivotal role during the
mTORC2 directly phosphorylates Akt. Together with the PDK1- acquirement of resistance [80-82], by decreasing the sensitivity of
mediated phosphorylation in the activation loop, phosphorylation of tumor cells to chemotherapy, by inhibiting apoptosis and by
Akt by mTORC2 is necessary for the full activation of Akt [9]. As sustaining survival, addition of PI3K inhibition to standard therapy
recently emerged, inhibition of the mTORC1 complex may increase may thus represent a novel and promising strategy to sensitize
Akt activity by disrupting the negative feedback on IRS-1 and tumor cells to chemotherapy and to overcome the issue of drug
therefore on the PI3K/Akt pathway [69, 70]. In this scenario, the resistance [83, 84].

dual PI3K-mTOR inhibition may have the possible advantage of
inhibiting at once PI3K, mTORC1 and mTORC2, thus effectively 3.4. Off-Target Effects of PI3K Inhibitors
turning off this pathway and overcoming the feedback inhibition Most of the PI3K inhibitors so far still show unspecific off-
normally observed with mTORC1 inhibitors. target effects due to the sequence similarity of the kinase domain of
The catalytic domains of the p110 subunits and mTOR are PI3Ks with the kinase domain of PIKKs such as mTOR and the
structurally similar, since they belong to the PIK-related kinase DNA-dependent protein kinase (DNA-PK) [85]. In addition, most
family. Several inhibitors, recently under evaluation in preclinical of the small molecule PI3K inhibitors developed so far are ATP-
and clinical studies, can inhibit both mTOR and all class I PI3K. competitive inhibitors. For instance, the prototypical pan-PI3K
inhibitor LY294002, derived from the flavonoid quercetin, inhibits
SF1126 also mTOR, DNA-PK, casein kinase 2 (CK2) and Pim-1.
SF1126 is a covalent conjugate of LY294002 containing a Wortmannin, a metabolite of Penicillium funiculosum, inhibits
peptide-based targeting group which increases the solubility of mTOR, DNA-PK and additional kinases such as myosin light chain
PI3K Inhibitors in Cancer Current Medicinal Chemistry, 2011 Vol. 18, No. 18 2679

kinase, albeit at higher concentrations than class I PI3Ks [86]. viability via Akt and mTOR [95]. In parallel, activation of PI3K
Novel compounds such as NVP-BEZ235 [87, 88], SF1126 and by GPCRs controls insulin secretion by coordinating its
GSK2126458 [89] show activity against PIKKs and in particular intracellular trafficking and secretory process [96].
against DNA-PK. This serine/threonine protein kinase has been In this scenario, pharmacological inhibition of class I PI3Ks can
associated with the repair of radiation-induced DNA damage and its impair glucose tolerance by (i) causing insulin resistance in skeletal
inhibition should result in increased DNA-damage mediated by muscle and fat, (ii) promoting inappropriate liver gluconeogenesis
radiotherapy. However, it is presently unclear whether DNA-PK and (iii) reducing insulin release from pancreatic -cells. Relevant
inhibition represents an advantage or disadvantage in cancer findings have been obtained in genetic models in vivo. Mice lacking
therapy. There are several reports showing that concurrent the PIK3R1 and PIK3R2 genes (encoding for PI3K regulatory
treatment with PI3K inhibitors and DNA-damaging drugs subunits p85
, p50
, p55
and p85), develop severe insulin
significantly increases apoptosis [90]. This could be explained by resistance and diabetes mellitus [97]. Furthermore, p110

the off-target inhibition of DNA-PK, which sensitizes target tumors heterozygous mice display retarded growth and an impaired
to chemotherapy or radiotherapy. Nonetheless, the DNA-damage response to the insulin-like growth factor-I (IGF-1). Reduced p110

induced by chemo- or radiotherapy is not only limited to tumor activity causes insulin resistance, as shown by increased fasting
cells, and DNA-PK inhibition may actually increase side-effects insulin, reduced glucose tolerance and impaired response to insulin
and secondary tumor rate in treated individuals. compared to control mice. The deficiency in PI3K
is paralleled by
The future design of more selective and “clean” PI3K inhibitors a similar reduction in Akt phosphorylation in liver, muscle and
should minimize eventual side effects resulting from off-target adipose tissues, confirming that PI3K
is the major contributor to
ligand binding. Nonetheless, even in the absence of off-target insulin-stimulated Akt activation in vivo [98]. While PI3K
is
effects, new generation PI3K inhibitors may retain adverse side strictly required for insulin-mediated responses in insulin-
effects resulting from the systemic inhibition of the PI3K signaling responsive tissues, the effects of insulin stimulation in the liver is
pathway. instead markedly influenced by PI3K. Indeed, mice expressing a
catalytically inactive p110 develop retarded growth and mild
4. PI3K INHIBITION IN NON-CANCER CELLS: insulin resistance caused by deregulated gluconeogenesis and
POTENTIAL CAVEATS FOR CLINICAL USE glycogen synthesis in the liver, where these mice show up-
regulation of gluconeogenic enzymes. Loss of a functional PI3K
PI3Ks are widely expressed in non-cancer cells and play a key also results in increased insulin secretion and compensatory
role in molecular pathways underlying several physiological pancreatic islet hyperplasia [29]. Similar findings have been
functions beyond cell proliferation and survival. While targeting obtained in mice harbouring a liver-specific deletion of PI3K [30].
PI3K/mTOR in cancer tissues is clinically desirable, the systemic Lastly, in line with a role for PI3K in insulin release, one study has
inhibition of this signaling pathway may cause a number of reported that PI3K knockout is associated with blunted insulin
undesired effects, particularly in the case of compounds devoid of secretion upon glucose administration, while overall glucose
isoform specificity. So far, clinical trials have only provided tolerance is preserved in these animals through increased
preliminary data on this critical issue. Instead, valuable pre-clinical compensatory insulin sensitivity [99].
information has been obtained by several animal and cellular
studies performed with pharmacological inhibitors and/or with In agreement with genetic models, pan-PI3K inhibitors such as
genetic models (knock-in, knock-out mice) lacking selective PI3K wortmannin and LY294002 have been shown to blunt insulin-
or mTOR isoforms. Based on these data, systemic PI3K/mTOR stimulated glucose-uptake in muscle cells and adipocytes in a dose-
inhibition can be predicted to particularly impact on glucose dependent manner [100, 101]. Similarly, the preferential inhibition
metabolism, the cardiovascular system, fertility and bone. of PI3K
(e.g. with PIK-90, PI-103 or PIK-75) can potently block
Additional data regarding the effect of PI3K blockade on the insulin-stimulated phosphorylation of Akt in adipocytes and
inflammation and immunity has been reviewed elsewhere [91, 92]. myotubes, as well as insulin-stimulated glucose uptake in vivo
Nonetheless, the existence and severity of side effects in humans [102]. Moreover, inhibition of PI3K
has been shown to impair
will ultimately depend on: (i) the degree of species-specificity, (ii) adipocyte differentiation [103]. Instead, selective inhibition of
the pharmacodynamic and pharmacokinetic properties of each drug PI3K alone has been found to leave both insulin-induced Akt
and therefore the entity of residual PI3K/mTOR activity in non- phosphorylation in myotubes and adipocytes and insulin-stimulated
cancer cells and tissues during pharmacological treatment, and (iii) glucose uptake in vivo unchanged [102]. Finally, ex vivo treatment
the individual tolerance and co-morbidities of treated patients. of human -cells with selective PI3K inhibitor AS605240
significantly impairs the process of recruitment and exocytosis of
Glucose Metabolism insulin granules [96]. Taken together, genetic and preclinical
pharmacological studies indicate that systemic inhibitors targeting
PI3Ks play an important role in glucose homeostasis by
both class IA and class IB PI3Ks carry the highest potential of
controlling the insulin sensitivity of skeletal muscle, fat and liver
causing diabetes mellitus in patients, as they impair both the
[93]. Briefly, activation of the insulin receptor (IR) engages class
peripheral response to insulin as well as the compensatory response
IA PI3Ks (PI3K
, PI3K) through IRS proteins, leading to PIP3-
of endocrine pancreas to insulin resistance. Indeed, perturbations of
dependent mobilization of downstream targets such as Akt. In turn,
glucose homeostasis have been already reported in human studies
Akt promotes the translocation of the glucose transporter GLUT4 at
the plasma membrane, leading to glucose uptake from the [45, 55]. While the diabetogeneic potential of these compounds in
bloodstream in insulin-responsive tissues. In skeletal muscle and lean and non-insulin resistant individuals is unknown, special
liver, Akt also releases the inhibitory activity of glucose synthase caution can be foreseen in patients with pre-existent insulin
kinase (GSK-3) on the glycogen synthase, thus promoting glycogen resistance and/or receiving high dose steroids.
synthesis [94]. In hepatocytes, PI3Ks suppress gluconeogenesis by One study has provided interesting data regarding the possible
down-regulating the gene expression of key gluconeogenic effect of PI3K inhibition on food intake. Interestingly, pre-
enzymes such as phosphoenolpyruvate carboxykinase (PEPCK) and treatment of mice with a PI3K
or PI3K inhibitor (PIK-75, TGX-
glucose-6-phosphatase (G-6-Pase) through modulation of forkhead 221) reduced the anorexigenic effect of insulin and leptin on the
transcription factors (FOXOs). Furthermore, PI3K signaling is hypothalamus [104]. As cancer patients are commonly anorexic,
operational in endocrine pancreas, involving both class IA and class especially in the context of advanced disease and in the course of
IB PI3K isoforms. In pancreatic -cells, autocrine activation of the chemotherapy, drugs targeting PI3Ks may exert beneficial effects
IR, recruiting PI3K
and PI3K, positively regulates cell size and on their nutritional balance.
2680 Current Medicinal Chemistry, 2011 Vol. 18, No. 18 Ciraolo et al.

Cardiovascular System spermatogenesis and oogenesis. In females, activation of the

PI3K/Akt/FOXO pathway by SCF regulates early follicular
PI3Ks are widely expressed in the cardiovascular system development by stimulating oocyte growth and by enhancing the
(including the myocardium, the vessel wall and circulating cells), proliferation and differentiation of surrounding granulosa cells
where they mediate cellular responses to a number of physiological [125-127]. Indeed, mutant females where PI3K activation by c-Kit
and pathological stimuli [105, 106]. However, clinically meaningful is blunted, fertility is impaired due to compromised follicle
side effects of PI3K inhibition may stem in particular from the development at the cuboidal stages. Furthermore, adult mutant
blockade of PI3K/Akt/mTOR signaling in cardiomyocytes. Cardiac females develop ovarian cysts and ovarian tubular hyperplasia
cells express both class IA PI3Ks (PI3K
and PI3K), engaged by [123]. In the testis, the PI3K/Akt signaling pathway is activated at
RTKs such as IGF-1, insulin and epidermal growth factor receptor, different steps of the spermatogenetic process by SCF and by
as well as class IB PI3K, activated by GPCRs such as -adrenergic another key regulator of spermatogenesis, the glial cell line derived
receptors. neurotrophic factor (GDNF) [128, 129]. Indeed, disruption of the c-
While the chronic activation of myocardial PI3K is Kit receptor domain mediating the molecular interaction with PI3K
maladaptive, several lines of evidence indicate that PI3K
is results in male sterility due to defective proliferation and meiosis,
essential for cardiomyocyte viability and growth via Akt/mTOR as well as to increased apoptosis of spermatogonia [123, 124].
and plays a key role in the process of cardiac hypertrophy [107- Moreover, c-Kit-induced PI3K signaling is active in Leydig cells,
111]. Moreover, IGF-1-induced Akt signaling has been shown to where it controls baseline and stimulated testosterone secretion
increase contractility by bursting calcium currents [112]. [130].
Importantly, mice expressing a dominant-negative PI3K
display A recent study has further shown that PI3K represents the
smaller hearts compared to wild types, but their cardiac function is main isoform involved in spermatogenesis. Male mice expressing a
normal under basal conditions [113]. Nonetheless, myocardial kinase-inactive PI3K develop oligo-azoospermia and defective
PI3K
exerts a major cardioprotective action, as the loss of PI3K
fertility due to testicular hypotrophy and impaired spermatogenesis,
has been shown to accelerate pathological ventricular remodeling while testosterone secretion is normal [131]. Instead, female mice
and the development of heart failure in several rodent models such lacking PI3K catalytic activity are receptive and fertile.
as primary myocardiopathy, myocardial infarction, chronic Histological studies of PI3K-inactive testes show a widespread
adrenergic stimulation and pressure overload [114, 115]. cell loss within spermatogenic tubules due to defective proliferation
Taken together, preclinical data obtained from genetic models and survival of pre and post-meiotic cells, while Leydig and Sertoli
have clearly indicated that anti-cancer treatments affecting cells are unchanged. This phenotype results from the absence of
myocardial PI3K
can be safe in patients with normal cardiac PI3K/Akt signaling upon stimulation of spermatogenic cells by
function. However, inhibition of PI3K
in cardiomyocytes may SCF. This is confirmed by the fact that genetic deletion of the PI3K
cause cardiac dysfunction or even overt heart failure when coupled binding site on c-Kit similarly causes testicular hypotrophy and
to pre-existent cardiac disease or in association with other azoospermia [123, 124]. In agreement with the genetic model,
conditions causing cardiac stress. These may include subclinical phosphorylation of Akt in spermatogones is significantly reduced in
ischemic heart disease, uncontrolled hypertension and co-treatment vitro by treatment with selective PI3K inhibitor TGX-221 [131].
with cardiac toxins such as anthracyclins or trastuzumab. Taken together, these data indicate that systemic treatment with
PI3Ks are expressed in platelets and mediate crucial signaling PI3K inhibitors reaching meaningful concentrations in the gonads
steps in platelet activation and aggregation [106]. In particular, may impair gametogenesis and fertility, particularly in the male. As
PI3K and PI3K are activated by G-protein coupled receptors such the spermatogenic stem cell population is unchanged by the absence
as ADP-responsive receptor P2Y12 [116]. In vivo, different studies of PI3K activity, these changes can be predicted to be reversible
have reported (i) impaired arterial thrombosis and reduced upon discontinuation of drugs inhibiting testicular PI3K, both in
susceptibility to venous thromboembolism in PI3K-deficient mice pre and post-pubertal patients.
[117, 118]. and (ii) resistance to arterial thrombosis in
megacaryocyte-specific PI3K-deficient mice [119]. In agreement Bone
with genetic models, inhibition of PI3K (with TGX-221) can
reduce in vivo thrombus formation [120]. Moreover, a PI3K
- PI3K signaling is implicated in the processes of bone formation
selective inhibitor (PIK-75) has been shown to blunt the adjuvant and resorption, by playing a role both in osteoclasts and osteoblasts
effect of IGF-1 on ADP-triggered platelet aggregation [121]. It [132]. In particular, PI3K
has emerged as the chief skeletal PI3K
must be pointed out that bleeding time is preserved in mice lacking isoform [133]. In osteoclasts, PI3Ks are activated by cytokines and
either PI3K or PI3K, as well as in mice treated with PI3K growth factors such as colony-stimulating factor 1 (CSF-1),
inhibitor TGX-221, indicating that neither PI3K isoform is strictly receptor activator of nuclear factor-kB (RANKL) and
VB3 integrin,
required for global hemostasis. However, punctual data regarding leading to osteoclast survival, development and motility. Indeed,
the effect of novel pan-PI3K inhibitors on global hemostasis are pan-PI3K and PI3K
inhibitors (PIK-75, PI-103) have been shown
currently lacking. Further studies are needed to address this issue, to blunt the process of bone resorption, but also to promote the
as the widespread inhibition of platelet PI3Ks may carry a differentiation and survival of osteoblasts [132-134]. In this
hemorrhagic risk, particularly in the case of patients affected by scenario, the net effect of PI3K inhibition on bone density in the
malignancy-related or chemotherapy-induced thrombocytopenia. case of long term treatments in humans is currently unknown, but
may be biologically relevant in special conditions such as bone
Fertility invasion by metastatic disease or multiple myeloma and
paraneoplastic hyperparathyroidism.
PI3K signaling plays a key role in embryonic stem cell (ESC)
pluripotency and self-renewal. In particular, PI3K has emerged as 5. CONCLUSION AND PERSPECTIVES
the main PI3K isoform regulating the pluripotency of mouse ESCs,
while PI3K
mostly regulates ESC proliferation [122]. In addition, Although most PI3K inhibitors currently undergoing clinical
PI3K signaling is required for the fertility of males and females, as evaluation are active on all class I PI3Ks, single PI3K isoforms
shown by the phenotype of mice carrying a mutation of the c-Kit have been shown to diversely control tumorigenesis. For instance,
receptor domain mediating the molecular interaction with PI3Ks PI3K is critical in the context of PTEN-loss (e.g. in breast and
[123, 124]. c-Kit is the tyrosine kinase receptor of the stem cell prostate cancer), PI3K seems to mediate cell proliferation in
factor (SCF) and plays a key role in primordial germ cell biology,
PI3K Inhibitors in Cancer Current Medicinal Chemistry, 2011 Vol. 18, No. 18 2681

hematological malignancies (e.g. non-Hodgkin’s lymphomas and [9] Sarbassov, D.D.; Guertin, D.A.; Ali, S.M.; Sabatini, D.M. Phosphorylation
chronic lymphocytic leukaemia) and PI3K
is the only PI3K and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005,
307(5712), 1098-1101.
isoform showing gain-of-function mutations and selectively [10] Gymnopoulos, M.; Elsliger, M.A.; Vogt, P.K. Rare cancer-specific mutations
controlling cancer angiogenesis [135]. As a general and non- in PIK3CA show gain of function. Proc. Natl. Acad. Sci. U. S. A. 2007,
specific inhibition of PI3Ks is more likely to result in side effects 104(13), 5569-5574.
and toxicity, isoform-specific inhibition of PI3K appears therefore [11] Samuels, Y.; Wang, Z.; Bardelli, A.; Silliman, N.; Ptak, J.; Szabo, S.; Yan,
as a promising strategy to improve tolerability while preserving H.; Gazdar, A.; Powell, S.M.; Riggins, G.J.; Willson, J.K.; Markowitz, S.;
clinical efficacy. This approach will gain particular benefit from a Kinzler, K.W.; Vogelstein, B.; Velculescu, V.E. High frequency of mutations
of the PIK3CA gene in human cancers. Science. 2004, 304(5670), 554.
widespread use of patient-tailored therapies taking into account the [12] Zhao, L.; Vogt, P.K. Helical domain and kinase domain mutations in
profile of mutations and the functional status of the PI3K pathway p110alpha of phosphatidylinositol 3-kinase induce gain of function by
in cancer specimens. However, isoform-specific inhibitors with different mechanisms. Proc. Natl. Acad. Sci. U. S. A. 2008, 105(7), 2652-
satisfactory pharmacokinetics are not yet ready for initial clinical 2657.
evaluation in human patients, as they require additional [13] Chaussade, C.; Cho, K.; Mawson, C.; Rewcastle, G.W.; Shepherd, P.R.
Functional differences between two classes of oncogenic mutation in the
development and validation in vitro and in animal models. Finally,
PIK3CA gene. Biochem. Biophys. Res. Commun. 2009, 381(4), 577-581.
future studies need to directly prove that the isoform-specific [14] Bader, A.G.; Kang, S.; Vogt, P.K. Cancer-specific mutations in PIK3CA are
strategy is actually non-inferior to pan-PI3K inhibition in the real oncogenic in vivo. Proc. Natl. Acad. Sci. U. S. A. 2006, 103(5), 1475-1479.
world. [15] Morrow, C.J.; Gray, A.; Dive, C. Comparison of phosphatidylinositol-3-
kinase signalling within a panel of human colorectal cancer cell lines with
As observed with other anti-cancer agents, treatment with PI3K mutant or wild-type PIK3CA. FEBS Lett. 2005, 579(23), 5123-5128.
inhibitors may be associated with the development of drug [16] Vasudevan, K.M.; Barbie, D.A.; Davies, M.A.; Rabinovsky, R.; McNear,
resistance. While preclinical studies have already identified C.J.; Kim, J.J.; Hennessy, B.T.; Tseng, H.; Pochanard, P.; Kim, S.Y.; Dunn,
potential mutations of p110
conferring resistance to inhibitors, the I.F.; Schinzel, A.C.; Sandy, P.; Hoersch, S.; Sheng, Q.; Gupta, P.B.; Boehm,
ATP-binding cleft of p110
appears less tolerant to hotspot J.S.; Reiling, J.H.; Silver, S.; Lu, Y.; Stemke-Hale, K.; Dutta, B.; Joy, C.;
Sahin, A.A.; Gonzalez-Angulo, A.M.; Lluch, A.; Rameh, L.E.; Jacks, T.;
mutations compared to other protein kinases [136]. This suggests Root, D.E.; Lander, E.S.; Mills, G.B.; Hahn, W.C.; Sellers, W.R.; Garraway,
that the PI3K structure may be less prone to mutations in this L.A. AKT-Independent Signaling Downstream of Oncogenic PIK3CA
region, which may reduce the clinical development of resistance to Mutations in Human Cancer. Cancer Cell. 2009, 16(1), 21-32.
p110
-targeted drugs. However, a thorough mutagenic screen of [17] Velasco, A.; Bussaglia, E.; Pallares, J.; Dolcet, X.; Llobet, D.; Encinas, M.;
p110
will be required to prove this conclusively. A possible way Llecha, N.; Palacios, J.; Prat, J.; Matias-Guiu, X. PIK3CA gene mutations in
to avoid the development of drug resistance is represented by drug endometrial carcinoma: correlation with PTEN and K-RAS alterations. Hum.
Pathol. 2006, 37(11), 1465-1472.
combination therapy. For instance, dual inhibition of PI3Ks and [18] Silvestris, N.; Tommasi, S.; Petriella, D.; Santini, D.; Fistola, E.; Russo, A.;
mTOR may result in improved clinical outcome. As activation of Numico, G.; Tonini, G.; Maiello, E.; Colucci, G. The dark side of the moon:
the PI3K/Akt/mTOR pathway in cancer is frequently accompanied the PI3K/PTEN/AKT pathway in colorectal carcinoma. Oncology. 2009, 77.
by the engagement or frank hyperactivity of mitogen activated Suppl. 1, 69-74.
protein kinase (MAPK) signaling, the concurrent broad spectrum [19] Bachman, K.E.; Argani, P.; Samuels, Y.; Silliman, N.; Ptak, J.; Szabo, S.;
Konishi, H.; Karakas, B.; Blair, B.G.; Lin, C.; Peters, B.A.; Velculescu, V.E.;
inhibition of PI3K/mTOR and MAPKs may further improve results
Park, B.H. The PIK3CA gene is mutated with high frequency in human
[137]. breast cancers. Cancer Biol. Ther. 2004, 3(8), 772-775.
[20] Saal, L.H.; Holm, K.; Maurer, M.; Memeo, L.; Su, T.; Wang, X.; Yu, J.S.;
ACKNOWLEDGEMENTS Malmstrom, P.O.; Mansukhani, M.; Enoksson, J.; Hibshoosh, H.; Borg, A.;
Parsons, R. PIK3CA mutations correlate with hormone receptors, node
This work was supported by grants from the Italian Association metastasis, and ERBB2, and are mutually exclusive with PTEN loss in
human breast carcinoma. Cancer Res. 2005, 65(7), 2554-2559.
for Cancer Research (AIRC), Fondazione Cariplo - Ricerca [21] Knobbe, C.B.; Reifenberger, G. Genetic alterations and aberrant expression
Biomedica 2009, Regione Piemonte - Ricerca Sanitaria Finalizzata of genes related to the phosphatidyl-inositol-3'-kinase/protein kinase B (Akt)
2009. signal transduction pathway in glioblastomas. Brain. Pathol. 2003, 13(4),
507-518.
[22] Benistant, C.; Chapuis, H.; Roche, S. A specific function for
REFERENCES
phosphatidylinositol 3-kinase alpha (p85alpha-p110alpha) in cell survival
and for phosphatidylinositol 3-kinase beta (p85alpha-p110beta) in de novo
[1] Hirsch, E.; Costa, C.; Ciraolo, E. Phosphoinositide 3-kinases as a common
platform for multi-hormone signaling. J. Endocrinol. 2007, 194(2), 243-256. DNA synthesis of human colon carcinoma cells. Oncogene. 2000, 19(44),
5083-5090.
[2] Katso, R.; Okkenhaug, K.; Ahmadi, K.; White, S.; Timms, J.; Waterfield,
M.D. Cellular function of phosphoinositide 3-kinases: implications for [23] Kang, S.; Denley, A.; Vanhaesebroeck, B.; Vogt, P.K. Oncogenic
transformation induced by the p110beta, -gamma, and -delta isoforms of
development, homeostasis, and cancer. Annu. Rev. Cell. Dev. Biol. 2001, 17,
class I phosphoinositide 3-kinase. Proc. Natl. Acad. Sci. U. S. A. 2006,
615-675.
[3] Schwindinger, W.F.; Robishaw, J.D. Heterotrimeric G-protein betagamma- 103(5), 1289-1294.
[24] Lee, S.H.; Poulogiannis, G.; Pyne, S.; Jia, S.; Zou, L.; Signoretti, S.; Loda,
dimers in growth and differentiation. Oncogene. 2001, 20(13), 1653-1660.
[4] Astle, M.V.; Horan, K.A.; Ooms, L.M.; Mitchell, C.A. The inositol M.; Cantley, L.C.; Roberts, T.M. A constitutively activated form of the
p110beta isoform of PI3-kinase induces prostatic intraepithelial neoplasia in
polyphosphate 5-phosphatases: traffic controllers, waistline watchers and
mice. Proc. Natl. Acad. Sci. U. S. A. 2010, 107(24), 11002-11007.
tumour suppressors? Biochem. Soc. Symp. 2007(74), 161-181.
[5] Ooms, L.M.; Horan, K.A.; Rahman, P.; Seaton, G.; Gurung, R.; Kethesparan, [25] Link, W.; Rosado, A.; Fominaya, J.; Thomas, J.E.; Carnero, A. Membrane
localization of all class I PI 3-kinase isoforms suppresses c-Myc-induced
D.S.; Mitchell, C.A. The role of the inositol polyphosphate 5-phosphatases in
cellular function and human disease. Biochem. J. 2009, 419(1), 29-49. apoptosis in Rat1 fibroblasts via Akt. J. Cell. Biochem. 2005, 95(5), 979-989.
[26] Edling, C.E.; Selvaggi, F.; Buus, R.; Maffucci, T.; Di Sebastiano, P.; Friess,
[6] Ma, K.; Cheung, S.M.; Marshall, A.J.; Duronio, V. PI(3,4,5)P3 and
PI(3,4)P2 levels correlate with PKB/akt phosphorylation at Thr308 and H.; Innocenti, P.; Kocher, H.M.; Falasca, M. Key role of phosphoinositide 3-
kinase class IB in pancreatic cancer. Clin. Cancer Res. 2010, 16(20), 4928-
Ser473, respectively; PI(3,4)P2 levels determine PKB activity. Cell Signal.
4937.
2008, 20(4), 684-694.
[7] Scheid, M.P.; Huber, M.; Damen, J.E.; Hughes, M.; Kang, V.; Neilsen, P.; [27] Carvalho, S.; Milanezi, F.; Costa, J.L.; Amendoeira, I.; Schmitt, F. PIKing
the right isoform: the emergent role of the p110beta subunit in breast cancer.
Prestwich, G.D.; Krystal, G.; Duronio, V. Phosphatidylinositol (3,4,5)P3 is
essential but not sufficient for protein kinase B (PKB) activation; Virchows Arch. 2010, 456(3), 235-243.
[28] Hill, K.M.; Kalifa, S.; Das, J.R.; Bhatti, T.; Gay, M.; Williams, D.; Taliferro-
phosphatidylinositol (3,4)P2 is required for PKB phosphorylation at Ser-473:
Smith, L.; De Marzo, A.M. The role of PI 3-kinase p110beta in AKT
studies using cells from SH2-containing inositol-5-phosphatase knockout
mice. J. Biol. Chem. 2002, 277(11), 9027-9035. signally, cell survival, and proliferation in human prostate cancer cells.
Prostate. 2010, 70(7), 755-764.
[8] Guertin, D.A.; Sabatini, D.M. Defining the role of mTOR in cancer. Cancer
Cell. 2007, 12(1), 9-22. [29] Ciraolo, E.; Iezzi, M.; Marone, R.; Marengo, S.; Curcio, C.; Costa, C.;
Azzolino, O.; Gonella, C.; Rubinetto, C.; Wu, H.; Dastru, W.; Martin, E.L.;
2682 Current Medicinal Chemistry, 2011 Vol. 18, No. 18 Ciraolo et al.

Silengo, L.; Altruda, F.; Turco, E.; Lanzetti, L.; Musiani, P.; Ruckle, T.; inhibitors exert distinct effects in solid tumors. Cancer Res. 2010, 70(3),
Rommel, C.; Backer, J.M.; Forni, G.; Wymann, M.P.; Hirsch, E. 1164-1172.
Phosphoinositide 3-kinase p110beta activity: key role in metabolism and [48] Salphati, L.; Wong, H.; Belvin, M.; Bradford, D.; Edgar, K.A.; Prior, W.W.;
mammary gland cancer but not development. Sci. Signal. 2008, 1(36), ra3. Sampath, D.; Wallin, J.J. Pharmacokinetic-pharmacodynamic modeling of
[30] Jia, S.; Liu, Z.; Zhang, S.; Liu, P.; Zhang, L.; Lee, S.H.; Zhang, J.; Signoretti, tumor growth inhibition and biomarker modulation by the novel
S.; Loda, M.; Roberts, T.M.; Zhao, J.J. Essential roles of PI(3)K-p110beta in phosphatidylinositol 3-kinase inhibitor GDC-0941. Drug. Metab. Dispos.
cell growth, metabolism and tumorigenesis. Nature. 2008, 454(7205), 776- 2010, 38(9), 1436-1442.
779. [49] Sos, M.L.; Fischer, S.; Ullrich, R.; Peifer, M.; Heuckmann, J.M.; Koker, M.;
[31] Wee, S.; Wiederschain, D.; Maira, S.M.; Loo, A.; Miller, C.; deBeaumont, Heynck, S.; Stuckrath, I.; Weiss, J.; Fischer, F.; Michel, K.; Goel, A.;
R.; Stegmeier, F.; Yao, Y.M.; Lengauer, C. PTEN-deficient cancers depend Regales, L.; Politi, K.A.; Perera, S.; Getlik, M.; Heukamp, L.C.; Ansen, S.;
on PIK3CB. Proc. Natl. Acad. Sci. U. S. A. 2008, 105(35), 13057-13062. Zander, T.; Beroukhim, R.; Kashkar, H.; Shokat, K.M.; Sellers, W.R.; Rauh,
[32] Sattler, M.; Verma, S.; Byrne, C.H.; Shrikhande, G.; Winkler, T.; Algate, D.; Orr, C.; Hoeflich, K.P.; Friedman, L.; Wong, K.K.; Pao, W.; Thomas,
P.A.; Rohrschneider, L.R.; Griffin, J.D. BCR/ABL directly inhibits R.K. Identifying genotype-dependent efficacy of single and combined PI3K-
expression of SHIP, an SH2-containing polyinositol-5-phosphatase involved and MAPK-pathway inhibition in cancer. Proc. Natl. Acad. Sci. U. S. A.
in the regulation of hematopoiesis. Mol. Cell. Biol. 1999, 19(11), 7473-7480. 2009, 106(43), 18351-18356.
[33] Fukuda, R.; Hayashi, A.; Utsunomiya, A.; Nukada, Y.; Fukui, R.; Itoh, K.; [50] Yao, E.; Zhou, W.; Lee-Hoeflich, S.T.; Truong, T.; Haverty, P.M.; Eastham-
Tezuka, K.; Ohashi, K.; Mizuno, K.; Sakamoto, M.; Hamanoue, M.; Tsuji, T. Anderson, J.; Lewin-Koh, N.; Gunter, B.; Belvin, M.; Murray, L.J.;
Alteration of phosphatidylinositol 3-kinase cascade in the multilobulated Friedman, L.S.; Sliwkowski, M.X.; Hoeflich, K.P. Suppression of
nuclear formation of adult T cell leukemia/lymphoma (ATLL). Proc. Natl. HER2/HER3-mediated growth of breast cancer cells with combinations of
Acad. Sci. U. S. A. 2005, 102(42), 15213-15218. GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab. Clin. Cancer Res.
[34] Horn, S.; Endl, E.; Fehse, B.; Weck, M.M.; Mayr, G.W.; Jucker, M. 2009, 15(12), 4147-4156.
Restoration of SHIP activity in a human leukemia cell line downregulates [51] Hoeflich, K.P.; Herter, S.; Tien, J.; Wong, L.; Berry, L.; Chan, J.; O'Brien,
constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3beta C.; Modrusan, Z.; Seshagiri, S.; Lackner, M.; Stern, H.; Choo, E.; Murray,
signaling and leads to an increased transit time through the G1 phase of the L.; Friedman, L.S.; Belvin, M. Antitumor efficacy of the novel RAF inhibitor
cell cycle. Leukemia. 2004, 18(11), 1839-1849. GDC-0879 is predicted by BRAFV600E mutational status and sustained
[35] Prasad, N.K.; Tandon, M.; Badve, S.; Snyder, P.W.; Nakshatri, H. extracellular signal-regulated kinase/mitogen-activated protein kinase
Phosphoinositol phosphatase SHIP2 promotes cancer development and pathway suppression. Cancer Res. 2009, 69(7), 3042-3051.
metastasis coupled with alterations in EGF receptor turnover. [52] Laird, D. XL765 targets tumor growth, survival, and angiogenesis in
Carcinogenesis. 2008, 29(1), 25-34. preclinical models by dual inhibition of PI3K and mTOR. 2007, AACR-NCI-
[36] Chow, K.U.; Nowak, D.; Kim, S.Z.; Schneider, B.; Komor, M.; Boehrer, S.; EORTC International Conference on Molecular Targets and Cancer
Mitrou, P.S.; Hoelzer, D.; Weidmann, E.; Hofmann, W.K. In vivo drug- Therapeutics.
response in patients with leukemic non-Hodgkin's lymphomas is associated [53] Carnero, A. Novel inhibitors of the PI3K family. Expert Opin. Investig.
with in vitro chemosensitivity and gene expression profiling. Pharmacol. Drugs. 2009, 18(9), 1265-1277.
Res. 2006, 53(1), 49-61. [54] Garcia-Echeverria, C. Protein and lipid kinase inhibitors as targeted
[37] Quade, B.J.; Wang, T.Y.; Sornberger, K.; Dal Cin, P.; Mutter, G.L.; Morton, anticancer agents of the Ras/Raf/MEK and PI3K/PKB pathways. Purinergic
C.C. Molecular pathogenesis of uterine smooth muscle tumors from Signal. 2009, 5(1), 117-125.
transcriptional profiling. Genes Chromosomes Cancer. 2004, 40(2), 97-108. [55] Shapiro, G.; Kwak, E.; Baselga, J.; Rodon, J.; Scheffold, C.; Laird, A.D.;
[38] Akada, M.; Crnogorac-Jurcevic, T.; Lattimore, S.; Mahon, P.; Lopes, R.; Bedell, C.; Edelman, G. Phase I dose-escalation study of XL147, a PI3K
Sunamura, M.; Matsuno, S.; Lemoine, N.R. Intrinsic chemoresistance to inhibitor administered orally to patients with solid tumors. J. Clin. Oncol.
gemcitabine is associated with decreased expression of BNIP3 in pancreatic 2009, 27(15), 3500.
cancer. Clin. Cancer Res. 2005, 11(8), 3094-3101. [56] Ihle, N.T.; Williams, R.; Chow, S.; Chew, W.; Berggren, M.I.; Paine-
[39] Kim, B.; Bang, S.; Lee, S.; Kim, S.; Jung, Y.; Lee, C.; Choi, K.; Lee, S.G.; Murrieta, G.; Minion, D.J.; Halter, R.J.; Wipf, P.; Abraham, R.; Kirkpatrick,
Lee, K.; Lee, Y.; Kim, S.S.; Yeom, Y.I.; Kim, Y.S.; Yoo, H.S.; Song, K.; L.; Powis, G. Molecular pharmacology and antitumor activity of PX-866, a
Lee, I. Expression profiling and subtype-specific expression of stomach novel inhibitor of phosphoinositide-3-kinase signaling. Mol. Cancer Ther.
cancer. Cancer Res. 2003, 63(23), 8248-8255. 2004, 3(7), 763-772.
[40] Ramaswamy, S.; Ross, K.N.; Lander, E.S.; Golub, T.R. A molecular [57] Ihle, N.T.; Paine-Murrieta, G.; Berggren, M.I.; Baker, A.; Tate, W.R.; Wipf,
signature of metastasis in primary solid tumors. Nat. Genet. 2003, 33(1), 49- P.; Abraham, R.T.; Kirkpatrick, D.L.; Powis, G. The phosphatidylinositol-3-
54. kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor
[41] Jaiswal, B.S.; Janakiraman, V.; Kljavin, N.M.; Chaudhuri, S.; Stern, H.M.; receptor inhibitor gefitinib in A-549 human non-small cell lung cancer
Wang, W.; Kan, Z.; Dbouk, H.A.; Peters, B.A.; Waring, P.; Dela Vega, T.; xenografts. Mol. Cancer Ther. 2005, 4(9), 1349-1357.
Kenski, D.M.; Bowman, K.K.; Lorenzo, M.; Li, H.; Wu, J.; Modrusan, Z.; [58] Howes, A.L.; Chiang, G.G.; Lang, E.S.; Ho, C.B.; Powis, G.; Vuori, K.;
Stinson, J.; Eby, M.; Yue, P.; Kaminker, J.S.; de Sauvage, F.J.; Backer, J.M.; Abraham, R.T. The phosphatidylinositol 3-kinase inhibitor, PX-866, is a
Seshagiri, S. Somatic mutations in p85alpha promote tumorigenesis through potent inhibitor of cancer cell motility and growth in three-dimensional
class IA PI3K activation. Cancer Cell. 2009, 16(6), 463-474. cultures. Mol. Cancer Ther. 2007, 6(9), 2505-2514.
[42] Berenjeno, I.M.; Vanhaesebroeck, B. PI3K regulatory subunits lose control [59] Jimeno, A.; Hong, D.S.; Hecker, S.; Clement, R.; Kurzrock, R.; Pestano,
in cancer. Cancer Cell. 2009, 16(6), 449-450. L.A.; Hiscox, A.; Leos, R.A.; Kirkpatrick, D.L.; Eckhardt, S.G.; Herbst, R.S.
[43] C.G.A.N. Comprehensive genomic characterization defines human Phase I trial of PX-866, a novel phosphoinositide-3-kinase (PI-3K) inhibitor.
glioblastoma genes and core pathways. Nature. 2008, 455(7216), 1061-1068. J. Clin. Oncol. 2009, 27(15), 3542.
[44] Sun, M.; Hillmann, P.; Hofmann, B.T.; Hart, J.R.; Vogt, P.K. Cancer-derived [60] Markman, B.; Atzori, F.; Perez-Garcia, J.; Tabernero, J.; Baselga, J. Status of
mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase PI3K inhibition and biomarker development in cancer therapeutics. Annals of
function through the catalytic subunit p110alpha. Proc. Natl. Acad. Sci. U. S. Oncology. 2010, 21(4), 683-691.
A. 2010, 107(35), 15547-15552. [61] Pacold, M.E.; Suire, S.; Perisic, O.; Lara-Gonzalez, S.; Davis, C.T.; Walker,
[45] Wagner, A.J.; Von Hoff, D.H.; LoRusso, P.M.; Tibes, R.; Mazina, K.E.; E.H.; Hawkins, P.T.; Stephens, L.; Eccleston, J.F.; Williams, R.L. Crystal
Ware, J.A.; Yan, Y.; Derynck, M.K.; Demetri, G.D. A first-in-human phase I structure and functional analysis of Ras binding to its effector
study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID phosphoinositide 3-kinase gamma. Cell. 2000, 103(6), 931-943.
in patients with advanced solid tumors. J. Clin. Oncol. 2009, 27(15), 3501. [62] Huang, C.H.; Mandelker, D.; Schmidt-Kittler, O.; Samuels, Y.; Velculescu,
[46] Folkes, A.J.; Ahmadi, K.; Alderton, W.K.; Alix, S.; Baker, S.J.; Box, G.; V.E.; Kinzler, K.W.; Vogelstein, B.; Gabelli, S.B.; Amzel, L.M. The
Chuckowree, I.S.; Clarke, P.A.; Depledge, P.; Eccles, S.A.; Friedman, L.S.; structure of a human p110alpha/p85alpha complex elucidates the effects of
Hayes, A.; Hancox, T.C.; Kugendradas, A.; Lensun, L.; Moore, P.; Olivero, oncogenic PI3Kalpha mutations. Science. 2007, 318(5857), 1744-1748.
A.G.; Pang, J.; Patel, S.; Pergl-Wilson, G.H.; Raynaud, F.I.; Robson, A.; [63] Berndt, A.; Miller, S.; Williams, O.; Le, D.D.; Houseman, B.T.; Pacold, J.I.;
Saghir, N.; Salphati, L.; Sohal, S.; Ultsch, M.H.; Valenti, M.; Wallweber, Gorrec, F.; Hon, W.C.; Liu, Y.; Rommel, C.; Gaillard, P.; Ruckle, T.;
H.J.; Wan, N.C.; Wiesmann, C.; Workman, P.; Zhyvoloup, A.; Zvelebil, Schwarz, M.K.; Shokat, K.M.; Shaw, J.P.; Williams, R.L. The p110delta
M.J.; Shuttleworth, S.J. The identification of 2-(1H-indazol-4-yl)-6-(4- structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.
methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin -4-yl-thieno[3,2- Nat. Chem. Biol. 2010, 6(3), 244.
d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor [64] Brown, J.; Byrd, J.; Furman, R.; Flinn, I.; Benson, D.; Coutre, S.; Kahl, B.;
of class I PI3 kinase for the treatment of cancer. J. Med. Chem. 2008, 51(18), Wagner-Johnston, N.; Spurgeon, S.; Pratz, K.; Giese, N.; Yu, O.A. Clinical
5522-5532. activity in a phase 1 study of CAL-101, an isoform-selective inhibitor of
[47] Edgar, K.A.; Wallin, J.J.; Berry, M.; Lee, L.B.; Prior, W.W.; Sampath, D.; phosphatidylinositol 3-kinase p110delta, in patients with B-cell
Friedman, L.S.; Belvin, M. Isoform-specific phosphoinositide 3-kinase malignancies. J. Clin. Oncol. 2009, 27(15), 3543.
PI3K Inhibitors in Cancer Current Medicinal Chemistry, 2011 Vol. 18, No. 18 2683

[65] Herman, S.E.; Gordon, A.L.; Wagner, A.J.; Heerema, N.A.; Zhao, W.; [83] Poh, T.W.; Pervaiz, S. LY294002 and LY303511 sensitize tumor cells to
Flynn, J.M.; Jones, J.; Andritsos, L.; Puri, K.D.; Lannutti, B.J.; Giese, N.A.; drug-induced apoptosis via intracellular hydrogen peroxide production
Zhang, X.; Wei, L.; Byrd, J.C.; Johnson, A.J. The phosphatidylinositol 3- independent of the phosphoinositide 3-kinase-Akt pathway. Cancer Res.
kinase-{delta} inhibitor CAL-101 demonstrates promising pre-clinical 2005, 65(14), 6264-6274.
activity in chronic lymphocytic leukemia by antagonizing intrinsic and [84] Wallin, J.J.; Guan, J.; Prior, W.W.; Edgar, K.A.; Kassees, R.; Sampath, D.;
extrinsic cellular survival signals. Blood. 2010. Belvin, M.; Friedman, L.S. Nuclear phospho-Akt increase predicts synergy
[66] Ikeda, H.; Hideshima, T.; Fulciniti, M.; Perrone, G.; Miura, N.; Yasui, H.; of PI3K inhibition and doxorubicin in breast and ovarian cancer. Sci. Transl.
Okawa, Y.; Kiziltepe, T.; Santo, L.; Vallet, S.; Cristea, D.; Calabrese, E.; Med. 2010, 2(48), 48ra66.
Gorgun, G.; Raje, N.S.; Richardson, P.; Munshi, N.C.; Lannutti, B.J.; Puri, [85] Lempiainen, H.; Halazonetis, T.D. Emerging common themes in regulation
K.D.; Giese, N.A.; Anderson, K.C. PI3K/p110{delta} is a novel therapeutic of PIKKs and PI3Ks. EMBO J. 2009, 28(20), 3067-3073.
target in multiple myeloma. Blood. 2010, 116(9), 1460-1468. [86] Gharbi, S.I.; Zvelebil, M.J.; Shuttleworth, S.J.; Hancox, T.; Saghir, N.;
[67] Harrington, L.S.; Findlay, G.M.; Gray, A.; Tolkacheva, T.; Wigfield, S.; Timms, J.F.; Waterfield, M.D. Exploring the specificity of the PI3K family
Rebholz, H.; Barnett, J.; Leslie, N.R.; Cheng, S.; Shepherd, P.R.; Gout, I.; inhibitor LY294002. Biochem. J. 2007, 404(1), 15-21.
Downes, C.P.; Lamb, R.F. The TSC1-2 tumor suppressor controls insulin- [87] Kong, D.; Yaguchi, S.; Yamori, T. Effect of ZSTK474, a novel
PI3K signaling via regulation of IRS proteins. J. Cell. Biol. 2004, 166(2), phosphatidylinositol 3-kinase inhibitor, on DNA-dependent protein kinase.
213-223. Biol. Pharm. Bull. 2009, 32(2), 297-300.
[68] Um, S.H.; Frigerio, F.; Watanabe, M.; Picard, F.; Joaquin, M.; Sticker, M.; [88] Maira, S.M.; Stauffer, F.; Brueggen, J.; Furet, P.; Schnell, C.; Fritsch, C.;
Fumagalli, S.; Allegrini, P.R.; Kozma, S.C.; Auwerx, J.; Thomas, G. Brachmann, S.; Chene, P.; De Pover, A.; Schoemaker, K.; Fabbro, D.;
Absence of S6K1 protects against age- and diet-induced obesity while Gabriel, D.; Simonen, M.; Murphy, L.; Finan, P.; Sellers, W.; Garcia-
enhancing insulin sensitivity. Nature. 2004, 431(7005), 200-205. Echeverria, C. Identification and characterization of NVP-BEZ235, a new
[69] Carracedo, A.; Ma, L.; Teruya-Feldstein, J.; Rojo, F.; Salmena, L.; Alimonti, orally available dual phosphatidylinositol 3-kinase/mammalian target of
A.; Egia, A.; Sasaki, A.T.; Thomas, G.; Kozma, S.C.; Papa, A.; Nardella, C.; rapamycin inhibitor with potent in vivo antitumor activity. Mol. Cancer Ther.
Cantley, L.C.; Baselga, J.; Pandolfi, P.P. Inhibition of mTORC1 leads to 2008, 7(7), 1851-1863.
MAPK pathway activation through a PI3K-dependent feedback loop in [89] Knight, S.D.; Adams, N.D.; Burgess, J.L.; Chaudhari, A.M.; Darcy, M.G.;
human cancer. J. Clin. Invest. 2008, 118(9), 3065-3074. Donatelli, C.A.; Luengo, J.I.; Newlander, K.A.; Parrish, C.A.; Ridgers, L.H.;
[70] Veilleux, A.; Houde, V.P.; Bellmann, K.; Marette, A. Chronic inhibition of Sarpong, M.A.; Schmidt, S.J.; Van Aller, G.S.; Carson, J.D.; Diamond,
the mTORC1/S6K1 pathway increases insulin-induced PI3K activity but M.A.; Elkins, P.A.; Gardiner, C.M.; Garver, E.; Gilbert, S.A.; Gontarek,
inhibits Akt2 and glucose transport stimulation in 3T3-L1 adipocytes. Mol. R.R.; Jackson, J.R.; Kershner, K.L.; Luo, L.; Raha, K.; Sherk, C.S.; Sung,
Endocrinol. 2010, 24(4), 766-778. C.-M.; Sutton, D.; Tummino, P.J.; Wegrzyn, R.J.; Auger, K.R.; Dhanak, D.
[71] Garlich, J.R.; De, P.; Dey, N.; Su, J.D.; Peng, X.; Miller, A.; Murali, R.; Lu, Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the
Y.; Mills, G.B.; Kundra, V.; Shu, H.K.; Peng, Q.; Durden, D.L. A vascular Mammalian Target of Rapamycin. ACS Med. Chem. Lett. 2010, 1(1), 39–43.
targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with [90] Westhoff, M.A.; Kandenwein, J.A.; Karl, S.; Vellanki, S.H.; Braun, V.;
antitumor and antiangiogenic activity. Cancer Res. 2008, 68(1), 206-215. Eramo, A.; Antoniadis, G.; Debatin, K.M.; Fulda, S. The
[72] Ozbay, T.; Durden, D.L.; Liu, T.; O'Regan, R.M.; Nahta, R. In vitro pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma
evaluation of pan-PI3-kinase inhibitor SF1126 in trastuzumab-sensitive and cells for apoptosis by inhibiting DNA repair. Oncogene. 2009, 28(40), 3586-
trastuzumab-resistant HER2-over-expressing breast cancer cells. Cancer 3596.
Chemother. Pharmacol. 2009, 65(4), 697-706. [91] Fruman, D.A.; Bismuth, G. Fine tuning the immune response with PI3K.
[73] Chiorean, E. G.; Mahadevan, D.; Harris, W. B.; Von Hoff, D. D.; Younger, Immunological Reviews. 2009, 228(1), 253-272.
A. E.; Rensvold, D. M.; Shelton, C. F.; Hennessy, B. T.; Garlich, J. R.; [92] Ghigo, A.; Damilano, F.; Braccini, L.; Hirsch, E. PI3K inhibition in
Ramanathan, R. K. Phase I evaluation of SF1126, a vascular targeted PI3K inflammation: Toward tailored therapies for specific diseases. Bioessays.
inhibitor, administered twice weekly IV in patients with refractory solid 2010, 32(3), 185-196.
tumors. J. Clin. Oncol. 2009, 27, 15s. [93] Braccini, L.; Ciraolo, E.; Morello, F.; Lu, X.; Hirsch, E. PI3K signaling: a
[74] Serra, V.; Markman, B.; Scaltriti, M.; Eichhorn, P.J.; Valero, V.; Guzman, crossroads of metabolic regulation. Expert Review of Endocrinology &
M.; Botero, M.L.; Llonch, E.; Atzori, F.; Di Cosimo, S.; Maira, M.; Garcia- Metabolism. 2009, 4(4), 349-357.
Echeverria, C.; Parra, J.L.; Arribas, J.; Baselga, J. NVP-BEZ235, a dual [94] Cross, D.A.; Alessi, D.R.; Cohen, P.; Andjelkovich, M.; Hemmings, B.A.
PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of Inhibition of glycogen synthase kinase-3 by insulin mediated by protein
cancer cells with activating PI3K mutations. Cancer Res. 2008, 68(19), kinase B. Nature. 1995, 378(6559), 785-789.
8022-8030. [95] Dickson, L.M.; Rhodes, C.J. Pancreatic beta-cell growth and survival in the
[75] Manara, M.C.; Nicoletti, G.; Zambelli, D.; Ventura, S.; Guerzoni, C.; onset of type 2 diabetes: a role for protein kinase B in the Akt? Am. J.
Landuzzi, L.; Lollini, P.L.; Maira, S.M.; Garcia-Echeverria, C.; Mercuri, M.; Physiol. Endocrinol. Metab. 2004, 287(2), E192-198.
Picci, P.; Scotlandi, K. NVP-BEZ235 as a new therapeutic option for [96] Pigeau, G.M.; Kolic, J.; Ball, B.J.; Hoppa, M.B.; Wang, Y.W.; Ruckle, T.;
sarcomas. Clin. Cancer Res. 2010, 16(2), 530-540. Woo, M.; Manning Fox, J.E.; MacDonald, P.E. Insulin granule recruitment
[76] Bhende, P.M.; Park, S.I.; Lim, M.S.; Dittmer, D.P.; Damania, B. The dual and exocytosis is dependent on p110gamma in insulinoma and human beta-
PI3K/mTOR inhibitor, NVP-BEZ235, is efficacious against follicular cells. Diabetes. 2009, 58(9), 2084-2092.
lymphoma. Leukemia. 2010. [97] Taniguchi, C.M.; Kondo, T.; Sajan, M.; Luo, J.; Bronson, R.; Asano, T.;
[77] LoRusso, P.; Markman, B.; Tabernero, J.; Shazer, R.; Nguyen, L.; Heath, E.; Farese, R.; Cantley, L.C.; Kahn, C.R. Divergent regulation of hepatic glucose
Patnaik, A.; Papadopoulos, K. A phase I dose-escalation study of the safety, and lipid metabolism by phosphoinositide 3-kinase via Akt and
pharmacokinetics (PK), and pharmacodynamics of XL765, a PKClambda/zeta. Cell Metab. 2006, 3(5), 343-353.
PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with [98] Foukas, L.C.; Claret, M.; Pearce, W.; Okkenhaug, K.; Meek, S.; Peskett, E.;
advanced solid tumors. Journal. of. Clinical. Oncology. 2009, 27(15), 3502. Sancho, S.; Smith, A.J.; Withers, D.J.; Vanhaesebroeck, B. Critical role for
[78] Gwak, H.S.; Shingu, T.; Chumbalkar, V.; Hwang, Y.H.; Dejournett, R.; the p110alpha phosphoinositide-3-OH kinase in growth and metabolic
Latha, K.; Koul, D.; Alfred Yung, W.K.; Powis, G.; Farrell, N.P.; Bogler, O. regulation. Nature. 2006, 441(7091), 366-370.
Combined action of the dinuclear platinum compound BBR3610 with the [99] MacDonald, P.E.; Joseph, J.W.; Yau, D.; Diao, J.; Asghar, Z.; Dai, F.; Oudit,
PI3-K inhibitor PX-866 in glioblastoma. Int. J. Cancer. 2011, 128(4), 787- G.Y.; Patel, M.M.; Backx, P.H.; Wheeler, M.B. Impaired glucose-stimulated
796. insulin secretion, enhanced intraperitoneal insulin tolerance, and increased
[79] Martin-Fernandez, C.; Bales, J.; Hodgkinson, C.; Welman, A.; Welham, beta-cell mass in mice lacking the p110gamma isoform of phosphoinositide
M.J.; Dive, C.; Morrow, C.J. Blocking phosphoinositide 3-kinase activity in 3-kinase. Endocrinology. 2004, 145(9), 4078-4083.
colorectal cancer cells reduces proliferation but does not increase apoptosis [100] Shepherd, P.R.; Nave, B.T.; Siddle, K. Insulin stimulation of glycogen
alone or in combination with cytotoxic drugs. Mol. Cancer Res. 2009, 7(6), synthesis and glycogen synthase activity is blocked by wortmannin and
955-965. rapamycin in 3T3-L1 adipocytes: evidence for the involvement of
[80] Lee, J.T., Jr.; Steelman, L.S.; McCubrey, J.A. Phosphatidylinositol 3'-kinase phosphoinositide 3-kinase and p70 ribosomal protein-S6 kinase. Biochem. J.
activation leads to multidrug resistance protein-1 expression and subsequent 1995, 305. (. Pt. 1), 25-28.
chemoresistance in advanced prostate cancer cells. Cancer Res. 2004, [101] Lee, A.D.; Hansen, P.A.; Holloszy, J.O. Wortmannin inhibits insulin-
64(22), 8397-8404. stimulated but not contraction-stimulated glucose transport activity in
[81] Kim, D.; Dan, H.C.; Park, S.; Yang, L.; Liu, Q.; Kaneko, S.; Ning, J.; He, L.; skeletal muscle. FEBS Lett. 1995, 361(1), 51-54.
Yang, H.; Sun, M.; Nicosia, S.V.; Cheng, J.Q. AKT/PKB signaling [102] Knight, Z.A.; Gonzalez, B.; Feldman, M.E.; Zunder, E.R.; Goldenberg, D.D.;
mechanisms in cancer and chemoresistance. Front. Biosci. 2005, 10, 975- Williams, O.; Loewith, R.; Stokoe, D.; Balla, A.; Toth, B.; Balla, T.; Weiss,
987. W.A.; Williams, R.L.; Shokat, K.M. A Pharmacological Map of the PI3-K
[82] Huang, W.C.; Hung, M.C. Induction of Akt activity by chemotherapy Family Defines a Role for p110[alpha] in Insulin Signaling. Cell. 2006,
confers acquired resistance. J. Formos. Med. Assoc. 2009, 108(3), 180-194. 125(4), 733-747.
2684 Current Medicinal Chemistry, 2011 Vol. 18, No. 18 Ciraolo et al.

[103] Kim, J.E.; Shepherd, P.R.; Chaussade, C. Investigating the role of class-IA [121] Kim, S.; Garcia, A.; Jackson, S.P.; Kunapuli, S.P. Insulin-like growth factor-
PI 3-kinase isoforms in adipocyte differentiation. Biochem. Biophys. Res. 1 regulates platelet activation through PI3-K{alpha} isoform. Blood. 2007,
Commun. 2009, 379(4), 830-834. 110(13), 4206-4213.
[104] Tups, A.; Anderson, G.M.; Rizwan, M.; Augustine, R.A.; Chaussade, C.; [122] Kingham, E.; Welham, M. Distinct roles for isoforms of the catalytic subunit
Shepherd, P.R.; Grattan, D.R. Both p110
and p110 Isoforms of of class-IA PI3K in the regulation of behaviour of murine embryonic stem
Phosphatidylinositol 3-OH-Kinase are Required for Insulin Signalling in the cells. J. Cell. Sci. 2009, 122(13), 2311-2321.
Hypothalamus. Journal of Neuroendocrinology. 2010, 22(6), 534-542. [123] Kissel, H.; Timokhina, I.; Hardy, M.P.; Rothschild, G.; Tajima, Y.; Soares,
[105] Oudit, G.Y.; Penninger, J.M. Cardiac regulation by phosphoinositide 3- V.; Angeles, M.; Whitlow, S.R.; Manova, K.; Besmer, P. Point mutation in
kinases and PTEN. Cardiovasc. Res. 2009, 82(2), 250-260. Kit receptor tyrosine kinase reveals essential roles for Kit signaling in
[106] Morello, F.; Perino, A.; Hirsch, E. Phosphoinositide 3-kinase signalling in spermatogenesis and oogenesis without affecting other Kit responses. EMBO
the vascular system. Cardiovasc. Res. 2009, 82(2), 261-271. J. 2000, 19(6), 1312-1326.
[107] Crackower, M.A.; Oudit, G.Y.; Kozieradzki, I.; Sarao, R.; Sun, H.; Sasaki, [124] Blume-Jensen, P.; Jiang, G.; Hyman, R.; Lee, K.F.; O'Gorman, S.; Hunter, T.
T.; Hirsch, E.; Suzuki, A.; Shioi, T.; Irie-Sasaki, J.; Sah, R.; Cheng, H.Y.; Kit/stem cell factor receptor-induced activation of phosphatidylinositol 3'-
Rybin, V.O.; Lembo, G.; Fratta, L.; Oliveira-dos-Santos, A.J.; Benovic, J.L.; kinase is essential for male fertility. Nat. Genet. 2000, 24(2), 157-162.
Kahn, C.R.; Izumo, S.; Steinberg, S.F.; Wymann, M.P.; Backx, P.H.; [125] Reddy, P.; Shen, L.; Ren, C.; Boman, K.; Lundin, E.; Ottander, U.; Lindgren,
Penninger, J.M. Regulation of myocardial contractility and cell size by P.; Liu, Y.-x.; Sun, Q.-y.; Liu, K. Activation of Akt (PKB) and suppression
distinct PI3K-PTEN signaling pathways. Cell. 2002, 110(6), 737-749. of FKHRL1 in mouse and rat oocytes by stem cell factor during follicular
[108] McMullen, J.R.; Shioi, T.; Huang, W.Y.; Zhang, L.; Tarnavski, O.; Bisping, activation and development. Developmental Biology. 2005, 281(2), 160-170.
E.; Schinke, M.; Kong, S.; Sherwood, M.C.; Brown, J.; Riggi, L.; Kang, [126] Liu, L.; Rajareddy, S.; Reddy, P.; Du, C.; Jagarlamudi, K.; Shen, Y.;
P.M.; Izumo, S. The insulin-like growth factor 1 receptor induces Gunnarsson, D.; Selstam, G.; Boman, K.; Liu, K. Infertility caused by
physiological heart growth via the phosphoinositide 3-kinase(p110alpha) retardation of follicular development in mice with oocyte-specific expression
pathway. J. Biol. Chem. 2004, 279(6), 4782-4793. of Foxo3a. Development. 2007, 134(1), 199-209.
[109] McMullen, J.R.; Shioi, T.; Zhang, L.; Tarnavski, O.; Sherwood, M.C.; Kang, [127] Liu, K.; Rajareddy, S.; Liu, L.; Jagarlamudi, K.; Boman, K.; Selstam, G.;
P.M.; Izumo, S. Phosphoinositide 3-kinase(p110alpha) plays a critical role Reddy, P. Control of mammalian oocyte growth and early follicular
for the induction of physiological, but not pathological, cardiac hypertrophy. development by the oocyte PI3 kinase pathway: New roles for an old timer.
Proc. Natl. Acad. Sci. U. S. A. 2003, 100(21), 12355-12360. Developmental Biology. 2006, 299(1), 1-11.
[110] O'Neill, B.T.; Kim, J.; Wende, A.R.; Theobald, H.A.; Tuinei, J.; Buchanan, [128] Serve, H.; Hsu, Y.C.; Besmer, P. Tyrosine residue 719 of the c-kit receptor is
J.; Guo, A.; Zaha, V.G.; Davis, D.K.; Schell, J.C.; Boudina, S.; Wayment, B.; essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase
Litwin, S.E.; Shioi, T.; Izumo, S.; Birnbaum, M.J.; Abel, E.D. A conserved and for c-kit-associated PI 3-kinase activity in COS-1 cells. J. Biol. Chem.
role for phosphatidylinositol 3-kinase but not Akt signaling in mitochondrial 1994, 269(8), 6026-6030.
adaptations that accompany physiological cardiac hypertrophy. Cell Metab. [129] Lee, J.; Kanatsu-Shinohara, M.; Inoue, K.; Ogonuki, N.; Miki, H.; Toyokuni,
2007, 6(4), 294-306. S.; Kimura, T.; Nakano, T.; Ogura, A.; Shinohara, T. Akt mediates self-
[111] Zhang, D.; Contu, R.; Latronico, M.V.; Zhang, J.; Rizzi, R.; Catalucci, D.; renewal division of mouse spermatogonial stem cells. Development. 2007,
Miyamoto, S.; Huang, K.; Ceci, M.; Gu, Y.; Dalton, N.D.; Peterson, K.L.; 134(10), 1853-1859.
Guan, K.L.; Brown, J.H.; Chen, J.; Sonenberg, N.; Condorelli, G. MTORC1 [130] Rothschild, G.; Sottas, C.M.; Kissel, H.; Agosti, V.; Manova, K.; Hardy,
regulates cardiac function and myocyte survival through 4E-BP1 inhibition M.P.; Besmer, P. A role for kit receptor signaling in Leydig cell
in mice. J. Clin. Invest. 2010, 120(8), 2805-2816. steroidogenesis. Biol. Reprod. 2003, 69(3), 925-932.
[112] Sun, H.; Kerfant, B.G.; Zhao, D.; Trivieri, M.G.; Oudit, G.Y.; Penninger, [131] Ciraolo, E.; Morello, F.; Hobbs, R.M.; Wolf, F.; Marone, R.; Iezzi, M.; Lu,
J.M.; Backx, P.H. Insulin-like growth factor-1 and PTEN deletion enhance X.; Mengozzi, G.; Altruda, F.; Sorba, G.; Guan, K.; Pandolfi, P.P.; Wymann,
cardiac L-type Ca2+ currents via increased PI3Kalpha/PKB signaling. Circ. M.P.; Hirsch, E. Essential role of the p110beta subunit of phosphoinositide
Res. 2006, 98(11), 1390-1397. 3-OH kinase in male fertility. Mol. Biol. Cell. 2010, 21(5), 704-711.
[113] Shioi, T.; Kang, P.M.; Douglas, P.S.; Hampe, J.; Yballe, C.M.; Lawitts, J.; [132] Golden, L.H.; Insogna, K.L. The expanding role of PI3-kinase in bone. Bone.
Cantley, L.C.; Izumo, S. The conserved phosphoinositide 3-kinase pathway 2004, 34(1), 3-12.
determines heart size in mice. EMBO. J. 2000, 19(11), 2537-2548. [133] Grey, A.; Chaussade, C.; Empson, V.; Lin, J.-M.; Watson, M.; O'Sullivan,
[114] McMullen, J.R.; Amirahmadi, F.; Woodcock, E.A.; Schinke-Braun, M.; S.; Rewcastle, G.; Naot, D.; Cornish, J.; Shepherd, P. Evidence for a role for
Bouwman, R.D.; Hewitt, K.A.; Mollica, J.P.; Zhang, L.; Zhang, Y.; Shioi, T.; the p110-[alpha] isoform of PI3K in skeletal function. Biochem. Biophys.
Buerger, A.; Izumo, S.; Jay, P.Y.; Jennings, G.L. Protective effects of Res. Commun. 2010, 391(1), 564-569.
exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated and [134] Martin, S.K.; Fitter, S.; Bong, L.F.; Drew, J.J.; Gronthos, S.; Shepherd, P.R.;
hypertrophic cardiomyopathy. Proc. Natl. Acad. Sci. U. S. A. 2007, 104(2), Zannettino, A.C.W. NVP-BEZ235, a dual pan class I PI3 kinase and mTOR
612-617. inhibitor, promotes osteogenic differentiation in human mesenchymal
[115] Lin, R.C.; Weeks, K.L.; Gao, X.M.; Williams, R.B.; Bernardo, B.C.; stromal cells. J. Bone Miner. Res. 2010, 25(10), 2126-2137.
Kiriazis, H.; Matthews, V.B.; Woodcock, E.A.; Bouwman, R.D.; Mollica, [135] Graupera, M.; Guillermet-Guibert, J.; Foukas, L.C.; Phng, L.K.; Cain, R.J.;
J.P.; Speirs, H.J.; Dawes, I.W.; Daly, R.J.; Shioi, T.; Izumo, S.; Febbraio, Salpekar, A.; Pearce, W.; Meek, S.; Millan, J.; Cutillas, P.R.; Smith, A.J.;
M.A.; Du, X.J.; McMullen, J.R. PI3K(p110 alpha) protects against Ridley, A.J.; Ruhrberg, C.; Gerhardt, H.; Vanhaesebroeck, B. Angiogenesis
myocardial infarction-induced heart failure: identification of PI3K-regulated selectively requires the p110alpha isoform of PI3K to control endothelial cell
miRNA and mRNA. Arterioscler. Thromb. Vasc. Biol. 2010, 30(4), 724-732. migration. Nature. 2008, 453(7195), 662-666.
[116] Canobbio, I.; Stefanini, L.; Cipolla, L.; Ciraolo, E.; Gruppi, C.; Balduini, C.; [136] Zunder, E.R.; Knight, Z.A.; Houseman, B.T.; Apsel, B.; Shokat, K.M.
Hirsch, E.; Torti, M. Genetic evidence for a predominant role of PI3K{beta} Discovery of drug-resistant and drug-sensitizing mutations in the oncogenic
catalytic activity in ITAM- and integrin-mediated signaling in platelets. PI3K isoform p110 alpha. Cancer Cell. 2008, 14(2), 180-192.
Blood. 2009, 114(10), 2193-2196. [137] Kinkade, C.W.; Castillo-Martin, M.; Puzio-Kuter, A.; Yan, J.; Foster, T.H.;
[117] Hirsch, E.; Bosco, O.; Tropel, P.; Laffargue, M.; Calvez, R.; Altruda, F.; Gao, H.; Sun, Y.; Ouyang, X.; Gerald, W.L.; Cordon-Cardo, C.; Abate-Shen,
Wymann, M.P.; Montrucchio, G. Resistance to thromboembolism in PI3Kg- C. Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-
deficient mice. FASEB J. 2001, 15(11), 2019-2021. refractory prostate cancer in a preclinical mouse model. J. Clin. Invest. 2008,
[118] Lian, L.; Wang, Y.; Draznin, J.; Eslin, D.; Bennett, J.S.; Poncz, M.; Wu, D.; 118(9), 3051-3064.
Abrams, C.S. The relative role of PLC{beta} and PI3K{gamma} in platelet [138] Asenjo, A.B.; Sosa, H. A mobile kinesin-head intermediate during the ATP-
activation. Blood. 2005, 106(1), 110-117. waiting state. Proc. Natl. Acad. Sci. U. S. A. 2009, 106(14), 5657-5662.
[119] Martin, V.; Guillermet-Guibert, J.; Chicanne, G.; Cabou, C.; Jandrot-Perrus, [139] O'Brien, C.; Wallin, J.J.; Sampath, D.; GuhaThakurta, D.; Savage, H.;
M.; Plantavid, M.; Vanhaesebroeck, B.; Payrastre, B.; Gratacap, M.-P. Punnoose, E.A.; Guan, J.; Berry, L.; Prior, W.W.; Amler, L.C.; Belvin, M.;
Deletion of the p110{beta} isoform of phosphoinositide 3-kinase in platelets Friedman, L.S.; Lackner, M.R. Predictive biomarkers of sensitivity to the
reveals its central role in Akt activation and thrombus formation in vitro and phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer
in vivo. Blood. 2010, 115(10), 2008-2013. preclinical models. Clin. Cancer Res. 2010, 16(14), 3670-3683.
[120] Jackson, S.P.; Schoenwaelder, S.M.; Goncalves, I.; Nesbitt, W.S.; Yap, C.L.; [140] Raynaud, F.I.; Eccles, S.A.; Patel, S.; Alix, S.; Box, G.; Chuckowree, I.;
Wright, C.E.; Kenche, V.; Anderson, K.E.; Dopheide, S.M.; Yuan, Y.; Folkes, A.; Gowan, S.; De Haven Brandon, A.; Di Stefano, F.; Hayes, A.;
Sturgeon, S.A.; Prabaharan, H.; Thompson, P.E.; Smith, G.D.; Shepherd, Henley, A.T.; Lensun, L.; Pergl-Wilson, G.; Robson, A.; Saghir, N.;
P.R.; Daniele, N.; Kulkarni, S.; Abbott, B.; Saylik, D.; Jones, C.; Lu, L.; Zhyvoloup, A.; McDonald, E.; Sheldrake, P.; Shuttleworth, S.; Valenti, M.;
Giuliano, S.; Hughan, S.C.; Angus, J.A.; Robertson, A.D.; Salem, H.H. PI 3- Wan, N.C.; Clarke, P.A.; Workman, P. Biological properties of potent
kinase p110[beta]: a new target for antithrombotic therapy. Nat. Med. 2005, inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-
11(5), 507-514. 540, PI-620 to the oral agent GDC-0941. Mol. Cancer Ther. 2009, 8(7),
1725-1738.
PI3K Inhibitors in Cancer Current Medicinal Chemistry, 2011 Vol. 18, No. 18 2685

[141] Sutherlin, D.P.; Sampath, D.; Berry, M.; Castanedo, G.; Chang, Z.; [145] Bhatt, A.P.; Bhende, P.M.; Sin, S.H.; Roy, D.; Dittmer, D.P.; Damania, B.
Chuckowree, I.; Dotson, J.; Folkes, A.; Friedman, L.; Goldsmith, R.; Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine
Heffron, T.; Lee, L.; Lesnick, J.; Lewis, C.; Mathieu, S.; Nonomiya, J.; proliferative loops in PI3K/Akt/mTOR-addicted lymphomas. Blood. 2010,
Olivero, A.; Pang, J.; Prior, W.W.; Salphati, L.; Sideris, S.; Tian, Q.; Tsui, 115(22), 4455-4463.
V.; Wan, N.C.; Wang, S.; Wiesmann, C.; Wong, S.; Zhu, B.Y. Discovery of [146] Konstantinidou, G.; Bey, E.A.; Rabellino, A.; Schuster, K.; Maira, M.S.;
(thienopyrimidin-2-yl)aminopyrimidines as potent, selective, and orally Gazdar, A.F.; Amici, A.; Boothman, D.A.; Scaglioni, P.P. Dual
available pan-PI3-kinase and dual pan-PI3-kinase/mTOR inhibitors for the phosphoinositide 3-kinase/mammalian target of rapamycin blockade is an
treatment of cancer. J. Med. Chem. 2010, 53(3), 1086-1097. effective radiosensitizing strategy for the treatment of non-small cell lung
[142] Ihle, N.T.; Lemos, R., Jr.; Wipf, P.; Yacoub, A.; Mitchell, C.; Siwak, D.; cancer harboring K-RAS mutations. Cancer Res. 2009, 69(19), 7644-7652.
Mills, G.B.; Dent, P.; Kirkpatrick, D.L.; Powis, G. Mutations in the [147] McMillin, D.W.; Ooi, M.; Delmore, J.; Negri, J.; Hayden, P.; Mitsiades, N.;
phosphatidylinositol-3-kinase pathway predict for antitumor activity of the Jakubikova, J.; Maira, S.M.; Garcia-Echeverria, C.; Schlossman, R.; Munshi,
inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for N.C.; Richardson, P.G.; Anderson, K.C.; Mitsiades, C.S. Antimyeloma
resistance. Cancer Res. 2009, 69(1), 143-150. activity of the orally bioavailable dual phosphatidylinositol 3-
[143] Buonamici, S.; Williams, J.; Morrissey, M.; Wang, A.; Guo, R.; Vattay, A.; kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Cancer Res.
Hsiao, K.; Yuan, J.; Green, J.; Ospina, B.; Yu, Q.; Ostrom, L.; Fordjour, P.; 2009, 69(14), 5835-5842.
Anderson, D.L.; Monahan, J.E.; Kelleher, J.F.; Peukert, S.; Pan, S.; Wu, X.; [148] Lonial, S.; Harvey, R.D.; Francis, D.; Gul, E.; Jagannath, S.; Farag, S.; Hoth,
Maira, S.M.; Garcia-Echeverria, C.; Briggs, K.J.; Watkins, D.N.; Yao, Y.M.; D.; Frumento, R.; Garlich, J.R.; Trudel, S. Preliminary Results of a Phase I
Lengauer, C.; Warmuth, M.; Sellers, W.R.; Dorsch, M. Interfering with Study of the Pan-PI3 Kinase Inhibitor SF1126 in Patients with Relapsed and
resistance to smoothened antagonists by inhibition of the PI3K pathway in Refractory Myeloma. Blood. 2009, 114(22), 1492-1493.
medulloblastoma. Sci. Transl. Med. 2010, 2(51), 51ra70. [149] Chiorean, E.G.; Mahadevan, D.; Harris, W.B.; Von Hoff, D.D.; Younger,
[144] Lannutti, B.J.; Meadows, S.A.; Herman, S.E.; Kashishian, A.; Steiner, B.; A.E.; Rensvold, D.M.; Shelton, C.F.; Hennessy, B.T.; Garlich, J.R.;
Johnson, A.J.; Byrd, J.C.; Tyner, J.W.; Loriaux, M.M.; Deininger, M.; Ramanathan, R.K. Phase I evaluation of SF1126, a vascular targeted PI3K
Druker, B.J.; Puri, K.D.; Ulrich, R.G.; Giese, N.A. CAL-101, a p110{delta} inhibitor, administered twice weekly IV in patients with refractory solid
selective phosphatidylinositol-3-kinase inhibitor (PI3K) for the treatment of tumors. J. Clin. Oncol. 2009, 27(15), 2558.
B cell malignancies inhibits PI3K signaling and cellular viability. Blood.
2010.

Received: February 15, 2011 Revised: May 14, 2011 Accepted: May 15, 2011