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Review
PI3K signaling pathway targeting by using different molecular approaches to treat cancer Mohammad Rashid1*, Shahid Karim1, Babar Ali1, Shamshir Khan1, Makhmur Ahmad1, Asif Husain2, Ravinesh Mishra3 1. Department of Pharmaceutical Chemistry and Pharmacognosy, College of Pharmacy and Dentistry, Buraydah Colleges, Al-Qassim 31717, Kingdom of Saudi Arabia 2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi-110062, India 3. Institute of Pharmacy & Emerging Sciences, Baddi University of Emerging Science & Technology, Makhnumajra, Baddi, Solan-173205, Himachal Pradesh, India
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Abstract: Recent evidence of research has been proposed that the phosphoinositide 3-kinase (PI3K) pathway is noticeable target for searching novel anticancer agents. The phosphoinositide 3-kinase (PI3K) is accountable for harmonizing a diverse range of cell functions, such as transcription, proliferation, cell survival, cell growth, degranulation, vesicular trafficking and cell migration, which are mostly involved in carcinogenesis. Particularly, PI3K-mediated signaling molecules and its effects on gene expression contribute to tumorigenesis. PI3Ks generally are grouped into three distinct classes: I, II and III according to their structure and function. The class IA of PI3K includes an alpha, beta or delta p110 catalytic subunit (p110α, p110β, or p110γ), which are associated with the activation of RTKs. Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, have just been recognized as novel mechanisms of inducing oncogenic PI3K signaling. Therefore, the class IA PI3K is the only one of most evidently implicated in cancer. The PI3K pathway is mostly mutated in more cancer patients compared with normal person, making it an eye-catching molecular target for analyses based on inhibitor molecule. In this article, we highlighted the signaling effects and regulation pathway of PI3K involved in the development and survival of tumor cells. The consequence and intricacy of PI3K pathway made it an essential beneficial target for cancer treatment. Keywords: PI3K; AKT; mTOR; PDK-1; Tumor suppressor PTEN; Signal pathway
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CLC number: R965
Contents
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Document code: A
Article ID: 1003–1057(2017)9–621–14
1. Introduction ....................................................................................................................................................................... 622 2. Human cancer and PI3K signaling transduction ................................................................................................................ 623 3. Signaling transduction pathway of PI3K ........................................................................................................................... 623 4. PI3K signaling transduction as a drug target and their involvement in cancer .................................................................. 625 5. Catalytic and regulatory subunits of PI3K in signaling transduction pathway .................................................................. 626 5.1. Cell proliferation ............................................................................................................................................................ 626 5.2. Cell growth and size control ........................................................................................................................................... 627 5.3. Cell survival/inhibition of apoptosis ............................................................................................................................... 628 6. PI3K targeting drug development for cancer therapy ........................................................................................................ 629 7. Conclusions ...................................................................................................................................................................... 632 Acknowledgments ................................................................................................................................................................. 632 References ............................................................................................................................................................................. 632 Received: 2017-04-23, Revised: 2017-06-19, Accepted: 2017-08-25. * Corresponding author. Tel.: +966-577148790, E-mail:
[email protected] http://dx.doi.org/10.5246/jcps.2017.09.070 Copyright . 2017 Journal of Chinese Pharmaceutical Sciences, School of Pharmaceutical Sciences, Peking University
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(α and β) are expressed in all cells, but p110δ is
1. Introduction
primarily expressed in leukocytes and it has been Phosphoinositide 3 kinases (PI3Ks) are a family of
suggested that it evolves in parallel with the adaptive
enzymes and act as intracellular signaling transduction, and these signals are involved in cell functions, such as
immune system[12]. Class IB is composed of p101 regulatory and p110γ catalytic subunits and encoded
transcription, proliferation, cell survival, cell differentiation, cell growth, degranulation, cell migration, vesicular
by a single gene each[13–16]. The p85 regulatory subunits contain SH2 and SH3 domains, and SH2 domain can
trafficking and motility, leading to imbalance between
preferentially bind to phosphorylated tyrosine residues
oncogene PIK3CA and tumor suppressor PTEN[1–8].
in the amino acid sequence[17–20].
On the bases of substrate specificity and sequence
The class II includes three catalytic isoforms (C2α, C2β
homology, the PI3K enzymes are divided into four types
and C2γ) and catalyzes the production of PI(3)P from PI
of classes as follows: Class I, Class II, Class III and
and PI(3,4)P2 from PIP, which have an impact on immune
Class IV. Class I consists of regulatory and catalytic
body, but C2γ appears only in hepatocytes[3,15]. Class
subsets according to sequence. Class IA is composed of hetero dimer stuck between p110 catalytic subunit and of five variants of p85α, p55α, p50α, p85β and p55γ,
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p110α, β, or δ. The first three variants of regulatory subunit are encoded by the same gene (Pik3r1), and the remaining two are encoded by other genes, like Pik3r2
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and Pik3r3, p85β and p55γ, respectively. Among all
III is very similar in structure to Class I and composed
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p85 regulatory subunit. The p85 regulatory subunit consists and p110 catalytic subunit includes three variants of
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cells. C2α and C2β isoforms communicate throughout the
subunits and can be further subdivided IA and IB
of heterodimers of a catalytic (Vps34) and a regulatory (Vps15/p150) subunits. Class III catalyzes the production of PI(3)P from PI and is involved in the trafficking of proteins and vesicles[21]. Class IV is involved in ataxia telangiectasia, Rad3-related (ATR), DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia-mutated (ATM) and mammalian target of rapamycin (mTOR)[21]. Class
the regulatory subunits, the p85α is highly expressed[9].
IV includes the protein serine/threonine kinases and is
The three catalytic subunits are encoded by separate
referred to class IV PI 3-kinases. Table 1 shows the
genes, like Pik3ca, Pik3cb and Pik3cd for p110α, p110β
details of phosphatidylinositol-3 kinase classes, subunits,
[10,11]
and p110δ, respectively
. The first two p110 isoforms
isoforms, proteins and genes[3,10,15,17–23].
Table 1. Phosphatidylinositol-3 kinase classes, subunit, proteins, genes and amino acid sequences. Class Class 1 Catalytic
Class 1 Regulatory
Class 2
Class 3
Chromosomal location
Sequence length (AA)
PIK3CA
Gene
Alpha polypeptide
Protein
p110-α
Aliases
3q26.3
1068
PIK3CB
Beta polypeptide
p110-β
3q22.3
1070
PIK3CG
Gamma polypeptide
p110-γ
7q22.3
1102
PIK3CD
Delta polypeptide
p110-δ
1p36.2
1044
PIK3R1
Regulatory subunit 1 (α)
p85-α
5q13.1
724
PIK3R2
Regulatory subunit 2 (β)
p85-β
19p13.1
728
PIK3R3
Regulatory subunit 3 (γ)
p55-γ
1p34.1
461
PIK3R4
Regulatory subunit 4
p150
15p13.1
578
PIK3R5
Regulatory subunit 5
p101
17p13.1
880
PIK3R6
Regulatory subunit 6
p87
17p13.1
754
PIK3C2A
Alpha polypeptide
PI3K-C2α
11p15.1
1686
PIK3C2B
Beta polypeptide
PI3K-C2β
1q32.1
1634
PIK3C2G
Gamma polypeptide
PI3K-C2γ
12p12.3
1445
PIK3C3
Catalytic subunit
hVps34
18q12.3
887
PIK3R4
Regulatory subunit
P150
3q22.1
1358
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of pathophysiological, physiological and biological
2. Human cancer and PI3K signaling transduction
responses of cell cycle, and the uses of inhibitor of Human cancers appear as the result of multiple genetic
this signal produce anti-proliferating effects[27].
and epigenetic aberrations that allow the proto-cancer cell
The PI3K/AKT/mTOR signaling pathway is an
to escape normal social control. Many signal transduction
important pathway in regulating the cell cycle, which
pathways become constitutively active during this
has been linked with cellular quiescence, proliferation,
process, one of them with tremendous importance
cancer and longevity[4,6,25,30]. After the phosphorylation,
involves phosphoinositide3-kinase (PI3-kinase)[2,5,24,25].
PI3K activates AKT, and then AKT affects a number
Their useful clinical products can interrelate with a
of downstream effects, such as CREB activation, p27
number of structural domains and activate them through
inhibition, localizing FOXO in the cytoplasm, PtdIns-3ps
targeting or modulation of enzymatic activity[5,15].
activation and mTOR activation, which can affect
Therefore, PI3Ks play a key role in different physiological
transcription of p70 or 4EBP1[31,32]. There are many
events, including cell proliferation, differentiation,
known factors that enhance the PI3K/AKT pathway,
apoptosis, cytoskeletal organization and membrane
including EGF, shh, IGF-1, insulin and CaM. The
trafficking
[3,6,10,26]
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. Recent studies have shown that
pathway is antagonized by various factors, including
chromosomal rearrangements are commonly found
PTEN, GSK3B and HB9 (Fig. 1)[33]. In many cancers,
in many human tumors, resulting in uncontrolled
this pathway is overactive, thus reducing apoptosis and
activation of PI3K signaling pathway. PI3K plays a
allowing proliferation[26,30,34].
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major role in tumor growth and also in a potential response of a tumor to cancer treatment[5,24,27].
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3. Signaling transduction pathway of PI3K
Currently, development of cancer therapeutics are
dependent on the identification and evaluation of ‘targeted’ drugs at specific molecular aspects in signaling pathways of cancer cells [15]. These signaling pathways are involved in controlling the cell cycle progression, motility,
The PI3Ks are associated with distinctive and
gene transcription, apoptosis and cell metabolism[35,36].
preserved household of intracellular lipid kinase enzymes,
Among these pathways, the phosphoinositide 3-kinase
including phosphorylated 3′-hydroxyl group of
PI3K pathway is considered highly relevant. The PI3K
[6,28,29]
. This
signaling pathway is a critical regulator of many cellular
phosphorylation reaction mainly induces the activation
processes that promote the transformation of a normal
of many intracellular signaling pathways that regulate
cell to a cancer cell [33]. Initiation of this signaling
cell functions, such as cell growth, differentiation, survival,
cascade commences with the phosphorylation of
phosphatidylinositol and phosphoinositide
[3,4,7,15]
.
phosphatidylinositol 4,5-bisphosphate (PIP2) to produce
The intracellular signaling proteins have progressed
phosphatidylinositol 3,4,5-triphosphate (PIP3), which
the facility to bind to the lipid products of PI3Ks and
results in cell proliferation, motility and survival, among
metabolism, polarity and vesicle trafficking
[25,29]
. Through the past decade,
and somatic alterations in the PI3K-AKT/mTOR pathway
it has been clearly shown that the PI3K signaling
have been documented in cancer cell lines and tumor
transduction becomes one of the most highly mutated
specimens (Table 2, these values taken from http://
systems in human cancers, underscoring its central role
www.sanger.ac.uk/genetics/CGP/cosmic)[1,14,22,26,33,38–40].
activate PI3K signaling
in human carcinogenesis[29]. The intracellular signaling
The PI3K/AKT pathway is a central regulator of normal
cascades initiated by and intersecting with PI3K are
cell physiology, and it integrates extracellular growth
complex and intricate. PI3K signal involves in a widespread
signals into an intracellular cascade, leading to increased
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Mohammad Rashid et al. / J. Chin. Pharm. Sci. 2017, 26 (9), 621–634
cellular metabolism, growth and proliferation[3,4,23,26].
the alteration in PI3K/AKT signaling transduction and
Different types of human cancers are related with
represented in Table 3[9,22,31,38,26,40– 43].
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Figure 1. PI3K-AKT signaling pathway in cancer. The phosphatidylinositol 3 kinase (PI3K) pathway is frequently altered in cancer. Firstgeneration inhibitors of mammalian target of rapamycin (mTOR) have been approved for the treatment of renal, pancreatic, ovary, breast and brain cancers. In addition, a large number of novel agents targeting PI3K or AKT as well as second generation mTOR inhibitors have been used in early clinical trials.
Table 2. Incidence of PTEN and PIK3CA mutations in human cancers. Percentage of tumors with mutation/number of samples Primary tumor tissue
PIK3CA PTEN
PIK3CA PTEN
%
#
%
#
Prostate
29
7
14
371
Breast
27
987
6
561
Endometrium
23
199
38
1467
Colon
15
1128
9
344
Urinary tract
17
162
9
142
Upper aero digestive tract
10
229
4
529
Ovary
8
670
8
574
Stomach
8
362
5
446
Liver
7
253
5
354
Esophagus
7
124
1
94
Pancreas
6
66
1
67
Central nervous system
5
808
20
2758
Hematopoietic and lymphoid tissue
4
510
6
866
Lung
3
537
8
548
Skin
3
149
17
555
Thyroid
2
186
5
591
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Table 3. Human cancers allied with the alteration in PI3K/AKT signaling transduction. Human cancer type Ovarian
Alteration in PI3K signaling transduction
drive the oncogenic transformation and chronic activation of downstream signaling by molecules, such as PKB,
Amplification of p110 α gene
S6K and 4E bp1, which are commonly seen in cancer
PI3K p85alpha Mutation
cells[16,45,51]. A large body of research into the cellular
Elevated AKT1 kinase activity AKT2 amplification
roles of PI3Ks has also further validated them as
PTEN Mutation
potential foci for cancer chemotherapy, and several
Loss of PTEN heterozygosity and silencing of remaining alleles
additional PI3K effectors controlling cell proliferation
PI3K CA associated with VEGF expression, Micro vessel invasion
and apoptosis have been described[2]. Furthermore,
Cervical
Amplification of p110 α gene
molecules important to the processes of metastasis,
Colorectal
Over expression of PI3K Class 1a
development of multi-drug resistance, angiogenesis and cell
Protein PI3K P85 alpha mutation PTEN mutation in tumors with microsatellite Instability Breast
growth (i.e. distinct to proliferation) have been found to
AKT2 amplification
with extensive pharmacological studies validating the
Loss of PTEN heterozygosity
therapeutic potential of targeting the PI3K/AKT/mTOR
AKT3 mRNA over expression and high enzyme activity in ER negative cancer Pancreatic
AKT2 amplification
Glioblastoma
PTEN mutation in 70% of advanced tumors PTEN mutation
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PTEN silencing Prostate
AKT1 amplification PTEN mutation
Loss of PTEN heterozygosity and silencing of remaining alleles Leukemia Lymphoma Gastric
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PTEN inactivation
AKT 1 amplification
Activation of PI3K via erbB-associated with dedifferentiation
Lung
PTEN inactivation
pathway for the treatment of cancer, kinase inhibitors
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PTEN mutation in high grab tumors Melanoma
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depend upon or to be driven by PI3K activity[30]. Along
Elevated akt1 kinase activity
4. PI3K signaling transduction as a drug target and their involvement in cancer
targeting significant knots of this pathway, including PI3K, AKT, mTOR and 3-phosphoinositide-dependent protein kinase-1 (PDK-1), keep arising and entering clinical studies[28,52–59].
The most well characterized product of this reaction is
phosphatidylinositol-3,4,5-trisphosphate or PIP3, which is a critical second messenger that recruits AKT for the activation of growth, proliferation and survival signaling[3,6,45,48,51,60]. PIP3 is negatively regulated by dephosphorylation through tumor suppressor, PTEN[38]. The production of PIP3 is a unique feature of the class I PI3Ks, which can be further divided into class IA and class IB. So far, only the class IA PI3Ks have been implicated in human cancer, but frequent genetic alter-
An enormous amount of work on PI3Ks indicates
ations in these enzymes and their pathway effectors
that there is an important role for PI3Ks in tumor
have made the PI3K pathway one of the most frequently
progression, particularly in the control of proliferation,
dysregulated pathways in cancer[3,16,39,48,54,61]. Currently,
survival and regulation of the potential oncogene
a significant effort has been made to develop pan-specific
PKB
[4,23,26,44,45]
. These links are further supported by
and isoform-specific PI3K inhibitors for the treatment
the studies showing that the tumor suppressor, PTEN
of cancer[45]. This pathway is unique since every major
is an antagonist of PI3K signaling and that somatic
node is frequently mutated or amplified in a wide variety
mutations of p110α (PIK3CA) are present in a variety of
of solid tumors[62]. Receptor tyrosine kinases upstream
cancers[26,46,50]. Nowadays, it is known that three of the
of PI3K, the p110α catalytic subunit of PI3K, the
most frequent mutations in cancer constitutively activate
downstream kinase, AKT and the negative regulator
PI3Ka when they are expressed in cells, and then they
PTEN are all frequently altered in cancer[32,63,64].
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5. Catalytic and regulatory subunits of PI3K in sig-
The pattern of this regulation is huge in favor of
naling transduction pathway
tumorigenesis, cell proliferation, growth and survival are enhanced and apoptosis is suppressed [6,11]. It is
The family of PI3K enzymes in mammalian cells can
possible to divide the cellular responses dependent on
be divided into three general classes. Type I PI3Ks are
or driven by type I PI3K activity into various functional
the best understood and key players in a substantial
classes relevant to tumorigenesis or its treatment though
intracellular signaling networks, including many growth
the underpinning signaling pathways are not fully
and survival factors, which regulate cell proliferation,
understood. However, none of the responses below are
growth, survival and apoptosis (Table 4)[6,8,23,39,42,43,65].
solely regulated by PI3K activity.
The PI3K/AKT and related pathways are important in internalizing the effects of external growth factors
5.1. Cell proliferation
and membrane tyrosine kinases [66]. Activation of
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membrane kinases, including epidermal growth
PI3K signals act amongst many others to regulate
factor receptor (EGFR), by external growth factors
cell proliferation. A large variety of growth factor
initiates receptor dimerization and subsequent events
receptors activate type I PI3Ks either directly or via
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to activate these intracellular pathways[42,55,67,68]. AKT is activated downstream of PI3K and has multiple targets. AKT and the cellular energy sensors LKB1 (STK11)
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and AMP-activated protein kinase (AMPK) exert
opposing effects on mammalian target of rapamycin (mTOR) which is activated by AKT
[52,63,69,70]
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. ERK,
extracellular signal regulated kinase; FKHR, forkhead; GDP, guanosine diphosphate; IRS, insulin receptor
associated tyrosine kinases, G-protein subunits or activation of Ras[66,72]. Potentially, tumourigenic PI3K signals can be antagonized by the PtdIns (The first clear evidence suggesting that a PtdInsP3 phosphatase, other than PTEN, has potential to act as a tumor suppressor[38,47,49]. A patient who carries a SHIP mutation in a form of leukemia is described, and the population of cells carrying the mutation became undetectable after
substrate; GSK3, glycogen synthase kinase 3; MAPK,
treatment.) P3 phosphatases PTEN and SHIP[73]. The
mitogen activated protein kinase; NF-κB, nuclear
PtdIns P3 effector PKB regulates a variety of molecules
factor-κB; PIP2, phosphatidylinositol-3,4-diphosphate;
controlling the cell cycle [47,50,63]. PKB-mediated
PIP3, phosphatidylinositol-3,4,5-triphosphate; PKC, protein
phosphorylation of the FOXO family of transcription
kinase C; STAT, signal transducer and activator of
factors enables 14:3:3 proteins to bind and sequester
transcription (Fig. 2)
[11, 42,43,45,53,71]
them into the cytosolic compartment. In the nucleus,
.
Table 4. Mammalian phosphoinositide-3-kinases (PI3Ks) subunits with respective genes. Mammalian PI3Ks
Catalytic subunits
Regulatory subunits
Name
Gene
Name
Gene
Type 1A PI3Ks PI3Kα PI3Kβ PI3K δ
PI3Kα PI3Kβ PI3K δ
PIK3CA PIK3CB PIK3CD
p85α p85β p55γ
PIK3R1 PIK3R2 PIK3R3
Type 1B PI3Ks PI3Kγ
p110 γ
PIK3CG
p101 p84
PIK3R5
PIK3C2A PIK3C2B PIK3C2G
None known None known None known
PIK3C3
p150
Type II PI3Ks Type II PI3Kα Type II PI3Kβ Type II PI3K γ Type III PI3K Type III PI3K
hVps 34
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T308 S473
Cell-cycle progression
Metabolism cell-cycle survival
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Cell-cycle cell survival metabolism DNA damage
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Survival
Nutrient response cell and organ size cell-cycle protein translation
Figure 2. Diagram signaling of phosphatidylinositol-3-kinase (PI3K)/AKT pathway involved in tumorigenesis. After activation by receptor tyrosine kinases or Ras, PI3K phosphorylates phosphatidylinositol 4,5-trisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which activates AKT and 3-phosphoinositide-dependent protein kinase (PDK). Besides direct activation by PIP3, AKT can also be activated by PDK. AKT inhibits glycogen synthesis kinase 3 (GSK3) which stabilizes cyclin D1 and blocks forkhead (FOXO)-mediated transcription of the cyclin-dependent kinase (CDK) inhibitor p27, promoting cell cycle progression. By inhibition of the Bcl2-antagonist of cell death (BAD), AKT enhances cell survival. Furthermore, AKT also controls protein synthesis and cell growth by phosphorylation of mammalian target of rapamycin (mTOR). mTOR phosphorylates p70S6kinase (p70S6K) and 4E-binding protein 1 (4E-BP1), leading to the phosphorylation of S6 and release of eIF4E, both of which promote translationof mRNA to synthesize protein for cell growth.
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ability of PKB to phosphorylate and inhibit GSK-3b, a repressor of cyclin D1 expression[4,51,75]. The products of tumor suppressor genes are marked blue in Figure 3. 5.2. Cell growth and size control PI3K signals act amongst a range of others defining the appropriateness of the environment for growth[76]. As an integrator of these signals, mTOR activates a variety of steps involved in protein synthesis but particularly favors production of key molecules, such as Myc
Figure 3. PI3K signal regulation in cell proliferation for tumorigenesis, and the products of tumor suppressor genes are marked in blue.
and cyclin D as well as the ribosomal proteins[60,58,77]. The tumor suppressor complex, consisting of tuberin and hamartin (the gene products of TSC2 and TSC1,
the FOXO proteins can suppress cyclin D1 expression
respectively), acts as a suppressor of the growth promoting
and promote expression of cell cycle inhibitors, such as
signals produced by mTOR[60,74,78]. The tuberin component
p27Kip1[48,74]. These signals are complemented by the
has GAP activity and therefore functionally antagonizes
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the small GTPase, Rheb. GTP-bound Rheb activates,
factors by promoting degradation of their a-subunits,
probably indirectly, mTOR. PKB can phosphorylate
in a process involving the production of VHL tumor
and inhibit the TSC2 gene product tuberin and hence
suppressor[49,67]. Important targets of HIF are the REDD
de-repress mTOR activity[51,66,72,79,80]. Recent work has
family, and these proteins probably indirectly drive
shown that mTOR is part of two distinct complexes
activation of TSC complex[82,83]. The products of tumor
that are conserved between yeast and mammals. One
suppressor genes are marked in blue. The identities of
complex contains Raptor and mLST8
[60,71]
. The latter
the most important regulators of the rapamycin-insensitive
complex is rapamycin insensitive and regulates both
mTOR complex are unclear. The high sensitivity of the
[80]
.
phosphorylation of S473 in PKB to Wortmannin indicates
A variety of signals indicate whether the metabolic
that a signal through the PI3K/PKB/Tuberin/Rheb-pathway
circumstances of the cell are appropriate for growth,
is likely to be important because mTOR is relatively
PKCa and possibly phosphorylation of S473 in PKB
[51,79]
. ATP levels are read by AMPK,
insensitive to Wortmannin [84]. This suggests that a
which is phosphorylated and activated by the tumor
potential positive feed-back loop would tend to switch
suppressor LKB-1 only when AMPK is bound to AMP.
mTOR signals to either high or, if conditions for growth
AMPK can phosphorylate and activate tuberin. Nutrients,
are poor, low levels.
impinge on mTOR
regulating mTOR/Raptor association and activity, and the mechanism is unclear but probably both via the
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TSC complex (Fig. 4)[7,60,78,81]. Hypoxia and several other [58]
cellular stresses can regulate mTOR . Oxygen inhibits the accumulation of the HIF family of transcription
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particularly amino acids, have an important role in
5.3. Cell survival/inhibition of apoptosis
PI3K signals are critical for cell survival, and PKB is
a critical link. Sequestration of FOX family members leads to reduced expression of pro-apoptotic proteins,
Figure 4. PI3K signal regulation in cell growth and size control for tumorigenesis, and the products of tumor suppressor genes are mark ed in blue. Copyright . 2017 Journal of Chinese Pharmaceutical Sciences, School of Pharmaceutical Sciences, Peking University
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become a major focus of attention because of its critical role in controlling the cell cycle progression, motility, gene transcription, apoptosis, protein synthesis and cell metabolism[35,36]. The dysregulation of the PI3K/Akt signaling pathway is concerned in human diseases, including cancer, diabetes, cardiovascular disease and neurological diseases. In cancer, two mutations that increase the intrinsic kinase activity of PI3K have been identified. In addition, PTEN is frequently mutated or lost in human tumors. Activating mutations in Akt Figure 5. PI3K signal regulation in cell survival/inhibition of apoptosis for tumorigenesis, and the products of tumor suppressor genes are marked in blue.
have also been described. The frequency with which
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dysregulated Akt signaling contributes to human disease has culminated in the aggressive development of small molecule inhibitors of PI3K and Akt[23,27,41–44].
like Bim and Fas-ligand. PKB-mediated phosphorylation
The Akt signaling cascade is activated by receptor
of Bad leads to its sequestration by 14:3:3 proteins,
tyrosine kinases, integrins, B and T cell receptors,
leading to de-repression of the pro-survival molecule
cytokine receptors, G-protein-coupled receptors and other
[26,51,63,74]
BclXL
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. Similar negative regulation of YAP
stimuli that induce production of phospha-tidylinositol
leads to repression of the p53-related transcription factor
(3,4,5) trisphosphates (PIP3) by phosphoinositide 3-kinase
p73 and reduced expression of the pro-apoptotic
(PI3K). These lipids provide plasma membrane docking
protein Bax. Phosphorylation of IKK and Mdm2 leads to
sites for proteins that harbor pleckstrin-homology (PH)
functionally complementary, reciprocal changes in the
domains, including Akt and its upstream activator PDK1.
classic NF-kB pro-survival pathway and the pro-apoptotic
At the membrane, PDK1 phosphorylates Akt at Thr308
p53 pathway
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[14,37,63]
. PKB activation also leads to a
foremost to limit activation of Akt. The phosphorylation
stimulation of glycolysis and production of lactate
of Akt at Ser473 by mTORC2 excites full enzymatic
without any change in oxygen consumption, and this
activity. The components of PI3K-related kinase (PIKK)
effect probably underlies the observation that cell
family, counting DNA-PK, can also phosphorylate
transformation leads to an acceleration of glycolytic
Akt at Ser473. Akt is dephosphorylated by protein
rate
[51,63,85]
. The products of tumor suppressor genes are
phosphatase 2A (PP2A) and the PH-domain leucine-
marked in blue. Counter-intuitively, this phenomenon
rich-repeat-containing protein phosphatases (PHLPP1/2).
appears to result from increased glucose uptake and
In addition, the tumor suppresses and tensin homolog
primary utilization over and above the immediate
(PTEN) inhibits Akt activity by dephosphorylating
demands for growth, resulting in increased production
PIP3[26,30,40].
of potential biosynthetic intermediates (Fig. 5)[4,85].
Akt regulates cell growth through its effects on the TSC1/TSC2 complex and mTORC signaling. Akt
6. PI3K targeting drug development for cancer therapy
contributes to cell proliferation via phosphorylation of the CDK inhibitors p21 and p27. Akt is a major mediator
Initially, PI3K targeting drug discovery was start with
of cell survival through direct inhibition of pro-apoptotic
the proto-oncogene, the serine/threonine kinase Akt
proteins like Bad or inhibition of pro-apoptotic signals
(also known as protein kinase B or PKB), and has
generated by transcription factors like FoxO. Akt is
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Mohammad Rashid et al. / J. Chin. Pharm. Sci. 2017, 26 (9), 621–634
critically involved in the regulation of metabolism
function[45,53]. More than 20 companies and academic
through activation of AS160 and PFKFB2. Akt contributes
centers have declared active programmers in this area
to cell migration and invasion via phosphorylation of
(Table 5)[16,30,46,53,55,56,65,86–91]. Despite major interest and
palladin and vimentin. Due to the critical role of
widespread screening, no drugs have been developed
AKT/PKB in regulating diverse cellular functions, it
to specifically target the pathway in cancer clinical trials,
is an important therapeutic target for the treatment of
and a number of drugs in clinical use or preclinical
human disease
[21,24,27,30,44,51]
.
evaluation originally developed for other purposes
A diverse type of human cancer is correlated with
or identified in non-PI3K pathway screening have
the variation in PI3K/AKT signal pathway, and an
been demonstrated to directly or indirectly target
enormous amount of work on PI3Ks indicates that
PI3K signaling [11]. These include mammalian target
there is an important role for PI3Ks in tumor progression,
of rapamycin (mTOR) inhibitors of the ‘rapalog’
particularly in the control of proliferation, survival and
family of rapamycin analogues, ether lipids (such as
regulation of the potential oncogene PKB
[26,43–45]
n c . ac
. The
Perifosine and Miltefosine) and inhibitors of epidermal
PI3K/AKT pathway is activated in cancer, making this
growth factor receptor (EGFR), HER2/neu, c-Kit,
an optimal target for therapy as it is easier to inhibit
platelet-derived growth factor receptor (PDGFR) and
. s cp
activation events than to replace lost tumor suppressor
[60,55,58,68,70]
BCR-ABL
j . w
Table 5. PI3K targeting drug development as approved or under clinical trial for cancer therapy. Signal pathway
Target PI3K α/mTOR
Position
Phase I
Millenium
Phase I
Novartis
Phase I/II
Novartis
Phase I/II
KN309
Piramed Piramed Cerylid Cerylid/Kinacia
Phase I
PDK1
XXX
Berlex Lilly ICOS Vertex
Preclinical
p110 δ (Specific)
Idelalisib(CAL-101)
Gilead
Launched/Approved
PI3Kδ, γ (Specific)
IPI-145
Infinity Pharmaceuticals
Phase III
Dual PI3K/mTOR
NVPBEZ235
Novartis
Phase I
PI3K-α
BYL719
Novartis
Phase I
PI3K α, γ
PX-866
Oncothyreon
Phase I/II
Pan-inhibitor
SF1126
Signal Rx
Phase I
p110-α,-β Selectivity over mTOR
BAY-80- 6946
Bayer
Phase III
PI3K/mTOR
SAR245409 (XL765)
Sanofi
Phase II
Pan PI3K p110-α,-β, -δ,-γ
XL-147 (AR245408 )
Sanofi
Phase II
Pan-PI3K
GSK1059615
Glaxo Smith Kline
Phase I
PI3K (δ)
CAL-101
Calistoga
Phase I
PI3K/mTOR
GSK2126458
Glaxo Smith Kline
Phase II
PI3K β
GSK2636771
Glaxo Smith Kline
Phase I/IIa
Pan-inhibitor Selectivity over mTOR
ZSTK474
Zenyaku
Phase II
PI3K β
AZD6482
Astra Zeneca
Phase I
PI3Kα specific Selectivity over mTOR
Buparlisib (BKM-120)
Novartis
Phase III
w w PI3K/mTOR PI3K/mTOR
P110δ P110α Pan-inhibitor
LY3023414
Company
Eli Lilly
PI3K-α
Direct
Examples
.
MLN 1117 BGT226 BEZ235
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Mohammad Rashid et al. / J. Chin. Pharm. Sci. 2017, 26 (9), 621–634
Table 5. Continued. Signal pathway
Target
Examples
Company
Position
p110-α, γ/mTOR
PF-05212384 (PKI-587)
Pfizer
Phase I/II
PI3K/mTOR
PF-04691502
Pfizer
Phase II
pan-PI3K/mTOR
SF1126
Semafore
Phase 1
PIK3 α, δ
GDC-0941
Genentech
Phase IB/II
PI3Ka
GDC-0032 (Taselisib)
Roche/Genentech
Phase II
PI3K/mTOR
GDC-0980
Genentech
Phase II
PI3K/mTOR
VS-5584
Verastem
Phase I
PI3K
Ly294002 Wortmannin analogues SF1124 SF1126 PEG Wortmannin PI-103 ZSTK474
Eli Lilly Prolx Semafore Semafore Echelon Wyeth Baxter
Phase I Preclinical Preclinical Preclinical Preclinical Preclinical Preclinical
AKT
Miltefosine
Zentaris GmbH
Phase III
Perifosine (KRX-0401)
Keryx/AeternaZentaris
Phase II
PX316
BioImage PROLX
Preclinical development
PBI-05204
Oleandrin Phoenix Biotechnology
Early clinical development
RX-0201
Rexahn Pharmaceuticals
Phase II
Glaxo Smith Kline
Early clinical development
Merck/Astra Zeneca
Phase II
Vio-Quest
Phase I/II
Arno
Phase I
Glaxo Smith Kline
Phase I/II
Arno
Phase I/II
AeternaZentaris QLT Abbott Novartis Vertex Roche Celgene Novartis Kinacia/Cerylid
Preclinical
MK2206 VQD-002 (API-2/TCN)
c j . w AR-42
GSK795
Direct
AR-67 (DB-67)
w w
Erucylphosphocholine ErPC AEZS-127
n c . ac
. s p
GSK690693
AKT/S6K
XL418
Exelixis
Phase I
Pan AKT
AZD5363
AstraZeneca
Phase I
PI3K/AKT
ONC-01910 (Rigosertib)
Onconova
Phase I/II
PH domain
Miltefosine
Zentaris
Approved
Perifosine
Keryx
Phase II
NIH Schering Merck Celgene
Preclinical
mTOR
Rapamycin (Sirolimus, Rapamune) CCI779 (Temsirolimus, Torisel) RAD 001 (Everolimus, Afinitor) AP23573 (Deforolimus, MK-8669) AP23841 AZD8055 OSI-027 NCT01196429 NCT00408655 NCT00703170
Wyeth Wyeth/NCI/CTEP Novartis Merck/Ariad Ariad Ariad AstraZeneca OSI NCI NCI NCI
Approved Phase III Phase II/III Approved/Phase III Preclinical Phase I/II Phase I Phase II Phase I Phase II Phase II
Growth factor receptors
EGFR HER2 Insulin Integrins
Multiple
Preclinical to approved
XL-418
Exelixis
Phase I
SrcAbl
Multiple
Preclinical
Indirect
Intracellular kinases
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Mohammad Rashid et al. / J. Chin. Pharm. Sci. 2017, 26 (9), 621–634
7. Conclusions
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w w
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Dr Mohammad Rashid undersigned and awarded his PhD degree under the department of Medicinal Chemistry of Jamia Hamdard (Hamdard University), New Delhi, India. His PhD research work was focused on ˜Studies on some heterocyclic compounds as potential anticancer agents. His research work has been recognizing in the National Science Day in Jamia Hamdard, New Delhi, India. The contribution and so far of my research has been published more than forty publication and review article with high impact and reputed journals. He also awarded many travel and poster award from ICMR, DST, CSIR, Eurotox and IUTOX for the presenting research work abroad. He two times GATE (Graduate Aptitude Test in Engineering) exam qualified with 98.15 percentile. He have been worked as Project Fellow, JRF and SRF, University Grant Commission, Government of India. Recently, he was awarded Young Scientist, from Science & Engineering Research Board (SERB) under Department of Science & Technology (DST), Government of India, New Delhi [Registration No. SERB/LS-1030/2013] on the project entitled as “Design and development of Cdc7 kinase inhibitors by targeting the ATP and Dbf4 binding sites of Cdc7 kinase protein”. Currently, he is working as Assistant Professor in the Department of Pharmaceutical Chemistry and Pharmacognocy, College of Pharmacy and Dentistry, Buraydah Colleges, Al-Qassim, Kingdom of Saudi Arabia. Copyright . 2017 Journal of Chinese Pharmaceutical Sciences, School of Pharmaceutical Sciences, Peking University
http://www.jcps.ac.cn