PI3K signaling pathway targeting by using different ...

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PIK3C3. Catalytic subunit. hVps34. 18q12.3. 887. PIK3R4. Regulatory subunit. P150. 3q22.1. 1358. Table 1. Phosphatidylinositol-3 kinase classes, subunit, ...
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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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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

Copyright . 2017 Journal of Chinese Pharmaceutical Sciences, School of Pharmaceutical Sciences, Peking University

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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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chemotherapeutic agents are widely used to inhibit the altered PI3K/AKT signaling pathways, so the

levels of cancer progression can be ultimately reduced.

w w

Especially, PI3K/AKT-mediated signaling molecules and its effects on gene expression contribute to tumorigenesis. Current evidence has suggested that the PI3K/AKT pathway is a visible target for novel effective and safe antineoplastic agents of cancer treatment.

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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

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