Target Information

Target General Information

Target ID

T80276 (Former ID: TTDNC00388)

Target Name

PI3-kinase alpha (PIK3CA)

Synonyms

p110alpha; Serine/threonine protein kinase PIK3CA; PtdIns3kinase subunit p110alpha; PtdIns3kinase subunit alpha; PtdIns-3-kinase subunit p110-alpha; PtdIns-3-kinase subunit alpha; Phosphoinositide3kinase catalytic alpha polypeptide; Phosphoinositide-3-kinase catalytic alpha polypeptide; Phosphatidylinositol 4,5bisphosphate 3kinase catalytic subunit alpha isoform; Phosphatidylinositol 4,5bisphosphate 3kinase 110 kDa catalytic subunit alpha; Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform; Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha; PI3kinase subunit alpha; PI3Kalpha; PI3K-alpha; PI3-kinase subunit alpha

Gene Name

PIK3CA

Target Type

Successful target

[1]

Disease

[+] 3 Target-related Diseases

Breast cancer [ICD-11: 2C60-2C6Y]

Follicular lymphoma [ICD-11: 2A80]

Malignant haematopoietic neoplasm [ICD-11: 2B33]

Function

Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Also has serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS. Plays a role in the positive regulation of phagocytosis and pinocytosis.

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BioChemical Class

Kinase

UniProt ID

PK3CA_HUMAN

EC Number

EC 2.7.1.153

Sequence

MPPRPSSGELWGIHLMPPRILVECLLPNGMIVTLECLREATLITIKHELFKEARKYPLHQ
LLQDESSYIFVSVTQEAEREEFFDETRRLCDLRLFQPFLKVIEPVGNREEKILNREIGFA
IGMPVCEFDMVKDPEVQDFRRNILNVCKEAVDLRDLNSPHSRAMYVYPPNVESSPELPKH
IYNKLDKGQIIVVIWVIVSPNNDKQKYTLKINHDCVPEQVIAEAIRKKTRSMLLSSEQLK
LCVLEYQGKYILKVCGCDEYFLEKYPLSQYKYIRSCIMLGRMPNLMLMAKESLYSQLPMD
CFTMPSYSRRISTATPYMNGETSTKSLWVINSALRIKILCATYVNVNIRDIDKIYVRTGI
YHGGEPLCDNVNTQRVPCSNPRWNEWLNYDIYIPDLPRAARLCLSICSVKGRKGAKEEHC
PLAWGNINLFDYTDTLVSGKMALNLWPVPHGLEDLLNPIGVTGSNPNKETPCLELEFDWF
SSVVKFPDMSVIEEHANWSVSREAGFSYSHAGLSNRLARDNELRENDKEQLKAISTRDPL
SEITEQEKDFLWSHRHYCVTIPEILPKLLLSVKWNSRDEVAQMYCLVKDWPPIKPEQAME
LLDCNYPDPMVRGFAVRCLEKYLTDDKLSQYLIQLVQVLKYEQYLDNLLVRFLLKKALTN
QRIGHFFFWHLKSEMHNKTVSQRFGLLLESYCRACGMYLKHLNRQVEAMEKLINLTDILK
QEKKDETQKVQMKFLVEQMRRPDFMDALQGFLSPLNPAHQLGNLRLEECRIMSSAKRPLW
LNWENPDIMSELLFQNNEIIFKNGDDLRQDMLTLQIIRIMENIWQNQGLDLRMLPYGCLS
IGDCVGLIEVVRNSHTIMQIQCKGGLKGALQFNSHTLHQWLKDKNKGEIYDAAIDLFTRS
CAGYCVATFILGIGDRHNSNIMVKDDGQLFHIDFGHFLDHKKKKFGYKRERVPFVLTQDF
LIVISKGAQECTKTREFERFQEMCYKAYLAIRQHANLFINLFSMMLGSGMPELQSFDDIA
YIRKTLALDKTEQEALEYFMKQMNDAHHGGWTTKMDWIFHTIKQHALN

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3D Structure

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PDB

HIT2.0 ID

T56IUI

Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

Alpelisib

Drug Info

Approved

Breast cancer

[2]

BAY 80-6946

Drug Info

Approved

Follicular lymphoma

[1]

Clinical Trial Drug(s)

[+] 8 Clinical Trial Drugs

Buparlisib

Drug Info

Phase 3

Breast cancer

[3], [4]

GDC-0032

Drug Info

Phase 3

Breast cancer

[5]

LY3023414

Drug Info

Phase 2

Solid tumour/cancer

[6]

MLN1117

Drug Info

Phase 1/2

Solid tumour/cancer

[7]

PA-799

Drug Info

Phase 1/2

Colorectal cancer

[8]

BLY719

Drug Info

Phase 1

Solid tumour/cancer

[9]

HHCYH33

Drug Info

Phase 1

Breast cancer

[10]

PWT-33597

Drug Info

Phase 1

Solid tumour/cancer

[11]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 8 Inhibitor drugs

Alpelisib

Drug Info

[2]

BAY 80-6946

Drug Info

[1]

Buparlisib

Drug Info

[12]

MLN1117

Drug Info

[15]

PA-799

Drug Info

[16]

BLY719

Drug Info

[9]

HHCYH33

Drug Info

[17]

ETP-46321

Drug Info

[19]

Modulator

[+] 3 Modulator drugs

GDC-0032

Drug Info

[13]

LY3023414

Drug Info

[14]

PWT-33597

Drug Info

[18]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Drug Resistance
Mutation (DRM)

Drug Resistance Mutation Info

Target Affiliated Biological Pathways		Top
BioCyc	[+] 2 BioCyc Pathways	+
1	Superpathway of inositol phosphate compounds
2	3-phosphoinositide biosynthesis
KEGG Pathway	[+] 72 KEGG Pathways	+
1	Inositol phosphate metabolism
2	ErbB signaling pathway
3	Ras signaling pathway
4	Rap1 signaling pathway
5	cGMP-PKG signaling pathway
6	cAMP signaling pathway
7	Chemokine signaling pathway
8	HIF-1 signaling pathway
9	FoxO signaling pathway
10	Phosphatidylinositol signaling system
11	Sphingolipid signaling pathway
12	mTOR signaling pathway
13	PI3K-Akt signaling pathway
14	AMPK signaling pathway
15	Apoptosis
16	Adrenergic signaling in cardiomyocytes
17	VEGF signaling pathway
18	Osteoclast differentiation
19	Focal adhesion
20	Signaling pathways regulating pluripotency of stem cells
21	Platelet activation
22	Toll-like receptor signaling pathway
23	Jak-STAT signaling pathway
24	Natural killer cell mediated cytotoxicity
25	T cell receptor signaling pathway
26	B cell receptor signaling pathway
27	Fc epsilon RI signaling pathway
28	Fc gamma R-mediated phagocytosis
29	TNF signaling pathway
30	Leukocyte transendothelial migration
31	Neurotrophin signaling pathway
32	Cholinergic synapse
33	Inflammatory mediator regulation of TRP channels
34	Regulation of actin cytoskeleton
35	Insulin signaling pathway
36	Progesterone-mediated oocyte maturation
37	Estrogen signaling pathway
38	Prolactin signaling pathway
39	Thyroid hormone signaling pathway
40	Oxytocin signaling pathway
41	Regulation of lipolysis in adipocytes
42	Type II diabetes mellitus
43	Non-alcoholic fatty liver disease (NAFLD)
44	Aldosterone-regulated sodium reabsorption
45	Carbohydrate digestion and absorption
46	Bacterial invasion of epithelial cells
47	Chagas disease (American trypanosomiasis)
48	Toxoplasmosis
49	Amoebiasis
50	Hepatitis C
51	Hepatitis B
52	Measles
53	Influenza A
54	HTLV-I infection
55	Epstein-Barr virus infection
56	Pathways in cancer
57	Viral carcinogenesis
58	Proteoglycans in cancer
59	MicroRNAs in cancer
60	Colorectal cancer
61	Renal cell carcinoma
62	Pancreatic cancer
63	Endometrial cancer
64	Glioma
65	Prostate cancer
66	Melanoma
67	Chronic myeloid leukemia
68	Acute myeloid leukemia
69	Small cell lung cancer
70	Non-small cell lung cancer
71	Central carbon metabolism in cancer
72	Choline metabolism in cancer
Panther Pathway	[+] 19 Panther Pathways	+
1	Angiogenesis
2	Apoptosis signaling pathway
3	Axon guidance mediated by netrin
4	B cell activation
5	EGF receptor signaling pathway
6	Endothelin signaling pathway
7	FGF signaling pathway
8	Hypoxia response via HIF activation
9	Inflammation mediated by chemokine and cytokine signaling pathway
10	Insulin/IGF pathway-protein kinase B signaling cascade
11	Integrin signalling pathway
12	Interleukin signaling pathway
13	PDGF signaling pathway
14	PI3 kinase pathway
15	T cell activation
16	VEGF signaling pathway
17	p53 pathway
18	Ras Pathway
19	p53 pathway feedback loops 2
Pathwhiz Pathway	[+] 5 Pathwhiz Pathways	+
1	Inositol Metabolism
2	Phosphatidylinositol Phosphate Metabolism
3	Intracellular Signalling Through Adenosine Receptor A2a and Adenosine
4	Intracellular Signalling Through Adenosine Receptor A2b and Adenosine
5	Fc Epsilon Receptor I Signaling in Mast Cells
PID Pathway	[+] 61 PID Pathways	+
1	Fc-epsilon receptor I signaling in mast cells
2	BCR signaling pathway
3	ErbB4 signaling events
4	Insulin Pathway
5	GMCSF-mediated signaling events
6	Atypical NF-kappaB pathway
7	IL4-mediated signaling events
8	Plasma membrane estrogen receptor signaling
9	Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met)
10	Signaling events mediated by PTP1B
11	EPHB forward signaling
12	Osteopontin-mediated events
13	Reelin signaling pathway
14	Nectin adhesion pathway
15	TRAIL signaling pathway
16	CDC42 signaling events
17	Signaling events regulated by Ret tyrosine kinase
18	Signaling events mediated by TCPTP
19	Angiopoietin receptor Tie2-mediated signaling
20	FAS (CD95) signaling pathway
21	SHP2 signaling
22	Netrin-mediated signaling events
23	IL1-mediated signaling events
24	IL2-mediated signaling events
25	CXCR4-mediated signaling events
26	IGF1 pathway
27	EGF receptor (ErbB1) signaling pathway
28	IL5-mediated signaling events
29	Class I PI3K signaling events
30	IL2 signaling events mediated by PI3K
31	p75(NTR)-mediated signaling
32	E-cadherin signaling in the nascent adherens junction
33	Integrins in angiogenesis
34	IFN-gamma pathway
35	ErbB1 downstream signaling
36	ErbB2/ErbB3 signaling events
37	IL3-mediated signaling events
38	IL6-mediated signaling events
39	E-cadherin signaling in keratinocytes
40	PDGFR-beta signaling pathway
41	Neurotrophic factor-mediated Trk receptor signaling
42	Nephrin/Neph1 signaling in the kidney podocyte
43	IL23-mediated signaling events
44	PDGFR-alpha signaling pathway
45	Signaling events mediated by the Hedgehog family
46	Nongenotropic Androgen signaling
47	Internalization of ErbB1
48	CXCR3-mediated signaling events
49	VEGFR1 specific signals
50	Signaling events mediated by Stem cell factor receptor (c-Kit)
51	IL2 signaling events mediated by STAT5
52	Signaling events mediated by VEGFR1 and VEGFR2
53	PAR1-mediated thrombin signaling events
54	a6b1 and a6b4 Integrin signaling
55	Ephrin B reverse signaling
56	N-cadherin signaling events
57	Trk receptor signaling mediated by PI3K and PLC-gamma
58	EPHA2 forward signaling
59	VEGFR3 signaling in lymphatic endothelium
60	FGF signaling pathway
61	Signaling events mediated by focal adhesion kinase
Reactome	[+] 28 Reactome Pathways	+
1	PI3K Cascade
2	GPVI-mediated activation cascade
3	Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
4	PI3K events in ERBB4 signaling
5	PIP3 activates AKT signaling
6	GAB1 signalosome
7	PI3K events in ERBB2 signaling
8	PI3K/AKT activation
9	Role of phospholipids in phagocytosis
10	Tie2 Signaling
11	Constitutive Signaling by Aberrant PI3K in Cancer
12	DAP12 signaling
13	Role of LAT2/NTAL/LAB on calcium mobilization
14	Nephrin interactions
15	Costimulation by the CD28 family
16	CD28 dependent PI3K/Akt signaling
17	G beta:gamma signalling through PI3Kgamma
18	G alpha (q) signalling events
19	G alpha (12/13) signalling events
20	VEGFA-VEGFR2 Pathway
21	Interleukin-3, 5 and GM-CSF signaling
22	Constitutive Signaling by EGFRvIII
23	PI-3K cascade:FGFR1
24	PI-3K cascade:FGFR2
25	PI-3K cascade:FGFR3
26	PI-3K cascade:FGFR4
27	Interleukin receptor SHC signaling
28	Regulation of signaling by CBL
WikiPathways	[+] 44 WikiPathways	+
1	Toll-like receptor signaling pathway
2	Serotonin HTR1 Group and FOS Pathway
3	DNA Damage Response (only ATM dependent)
4	G13 Signaling Pathway
5	Regulation of Actin Cytoskeleton
6	Insulin Signaling
7	IL-4 Signaling Pathway
8	Signaling of Hepatocyte Growth Factor Receptor
9	Transcriptional activation by NRF2
10	IL1 and megakaryotyces in obesity
11	Signaling by ERBB4
12	Signaling by ERBB2
13	Fc epsilon receptor (FCERI) signaling
14	PI Metabolism
15	Interleukin-2 signaling
16	Fcgamma receptor (FCGR) dependent phagocytosis
17	Signaling by SCF-KIT
18	DAP12 interactions
19	Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)
20	Gastrin-CREB signalling pathway via PKC and MAPK
21	PIP3 activates AKT signaling
22	Integrated Pancreatic Cancer Pathway
23	Prostate Cancer
24	Signaling Pathways in Glioblastoma
25	TSLP Signaling Pathway
26	Regulation of Microtubule Cytoskeleton
27	TSH signaling pathway
28	SREBP signalling
29	TCR signaling
30	Signaling by PDGF
31	Signaling by Insulin receptor
32	Signaling by FGFR
33	Signaling by EGFR
34	NGF signalling via TRKA from the plasma membrane
35	Nephrin interactions
36	Interleukin-3, 5 and GM-CSF signaling
37	GPVI-mediated activation cascade
38	GPCR downstream signaling
39	Costimulation by the CD28 family
40	Cell surface interactions at the vascular wall
41	MicroRNAs in cardiomyocyte hypertrophy
42	Angiogenesis
43	Regulation of toll-like receptor signaling pathway
44	AMPK Signaling

References

Top

REF 1

2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.

REF 2

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019

REF 3

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7878).

REF 4

ClinicalTrials.gov (NCT01610284) Phase III Study of BKM120/Placebo With Fulvestrant in Postmenopausal Patients With Hormone Receptor Positive HER2-negative Locally Advanced or Metastatic Breast Cancer Refractory to Aromatase Inhibitor. U.S. National Institutes of Health.

REF 5

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 6

ClinicalTrials.gov (NCT02549989) Study of LY3023414 for the Treatment of Recurrent.

REF 7

ClinicalTrials.gov (NCT02393209) Docetaxel With or Without MLN1117 in Participants With Locally Advanced or Metastatic Non-small Cell Lung Cancer. U.S. National Institutes of Health.

REF 8

ClinicalTrials.gov (NCT04495621) MEN1611 With Cetuximab in Metastatic Colorectal Cancer (C-PRECISE-01) (C-PRECISE-01). U.S. National Institutes of Health.

REF 9

In vitro anticancer activity of PI3K alpha selective inhibitor BYL719 in head and neck cancer. Anticancer Res. 2015 Jan;35(1):175-82.

REF 10

ClinicalTrials.gov (NCT04856371) Study of CYH33 in Combination With Endocrine Therapy With or Without Palbociclib in Patients With HR+, HER2- Advanced Breast Cancer. U.S. National Institutes of Health.

REF 11

ClinicalTrials.gov (NCT01407380) Study of PWT33597 Mesylate in Subjects With Advanced Malignancies. U.S. National Institutes of Health.

REF 12

Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009 Aug;8(8):627-44.

REF 13

Company report (BioOncology)

REF 14

Company report (Lilly)

REF 15

National Cancer Institute Drug Dictionary (drug id 714372).

REF 16

The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011 May 15;17(10):3272-81.

REF 17

Adaptive resistance to PI3Kalpha-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC cells. Cell Death Dis. 2021 Jan 14;12(1):85.

REF 18

Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

REF 19

ETP-46321, a dual p110alpha/ class IA phosphoinositide 3-kinase inhibitor modulates T lymphocyte activation and collagen-induced arthritis. Biochem Pharmacol. 2016 Apr 15;106:56-69.

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