Target General Infomation
Target ID
T05031
Former ID
TTDI02297
Target Name
PI3K beta
Gene Name
PIK3CB
Synonyms
PI3Kbeta; PI3kinase subunit beta; Phosphatidylinositol 4,5bisphosphate 3kinase 110 kDa catalyticsubunit beta; Phosphatidylinositol 4,5bisphosphate 3kinase catalytic subunitbeta isoform; PtdIns3kinase subunit beta; PtdIns3kinase subunit p110beta; p110beta; PIK3CB
Target Type
Clinical Trial
Disease Breast cancer [ICD9: 174, 175; ICD10: C50]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Thrombosis [ICD9: 437.6, 453, 671.5, 671.9; ICD10: I80-I82]
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.Involved in the activation of AKT1 upon stimulation by G-protein coupled receptors (GPCRs) ligands such as CXCL12, sphingosine 1-phosphate, and lysophosphatidic acid. May also act downstream receptortyrosine kinases. Required in different signaling pathways for stable platelet adhesion and aggregation. Plays a role in platelet activation signaling triggered by GPCRs, alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) and ITAM (immunoreceptor tyrosine-based activation motif)-bearing receptors such as GP6. Regulates the strength of adhesion of ITGA2B/ ITGB3 activated receptors necessary for the cellular transmission of contractile forces. Required for platelet aggregation induced by F2 (thrombin) and thromboxane A2 (TXA2). Has a role in cell survival. May have a role in cell migration. Involved inthe early stage of autophagosome formation. Modulates the intracellular level of PtdIns3P (Phosphatidylinositol 3-phosphate) and activates PIK3C3 kinase activity. May act as a scaffold, independentlyof its lipid kinase activity to positively regulate autophagy. May have a role in insulin signaling as scaffolding protein in which the lipid kinase activity is not required. May have a kinase-independent function in regulating cell proliferation and in clathrin-mediated endocytosis. Mediator of oncogenic signal in cell lines lacking PTEN. The lipid kinase activity is necessary for its role in oncogenic transformation. Required for the growth of ERBB2 and RAS driven tumors.
BioChemical Class
Kinase
UniProt ID
EC Number
EC 2.7.1.153
Sequence
MCFSFIMPPAMADILDIWAVDSQIASDGSIPVDFLLPTGIYIQLEVPREATISYIKQMLW
KQVHNYPMFNLLMDIDSYMFACVNQTAVYEELEDETRRLCDVRPFLPVLKLVTRSCDPGE
KLDSKIGVLIGKGLHEFDSLKDPEVNEFRRKMRKFSEEKILSLVGLSWMDWLKQTYPPEH
EPSIPENLEDKLYGGKLIVAVHFENCQDVFSFQVSPNMNPIKVNELAIQKRLTIHGKEDE
VSPYDYVLQVSGRVEYVFGDHPLIQFQYIRNCVMNRALPHFILVECCKIKKMYEQEMIAI
EAAINRNSSNLPLPLPPKKTRIISHVWENNNPFQIVLVKGNKLNTEETVKVHVRAGLFHG
TELLCKTIVSSEVSGKNDHIWNEPLEFDINICDLPRMARLCFAVYAVLDKVKTKKSTKTI
NPSKYQTIRKAGKVHYPVAWVNTMVFDFKGQLRTGDIILHSWSSFPDELEEMLNPMGTVQ
TNPYTENATALHVKFPENKKQPYYYPPFDKIIEKAAEIASSDSANVSSRGGKKFLPVLKE
ILDRDPLSQLCENEMDLIWTLRQDCREIFPQSLPKLLLSIKWNKLEDVAQLQALLQIWPK
LPPREALELLDFNYPDQYVREYAVGCLRQMSDEELSQYLLQLVQVLKYEPFLDCALSRFL
LERALGNRRIGQFLFWHLRSEVHIPAVSVQFGVILEAYCRGSVGHMKVLSKQVEALNKLK
TLNSLIKLNAVKLNRAKGKEAMHTCLKQSAYREALSDLQSPLNPCVILSELYVEKCKYMD
SKMKPLWLVYNNKVFGEDSVGVIFKNGDDLRQDMLTLQMLRLMDLLWKEAGLDLRMLPYG
CLATGDRSGLIEVVSTSETIADIQLNSSNVAAAAAFNKDALLNWLKEYNSGDDLDRAIEE
FTLSCAGYCVASYVLGIGDRHSDNIMVKKTGQLFHIDFGHILGNFKSKFGIKRERVPFIL
TYDFIHVIQQGKTGNTEKFGRFRQCCEDAYLILRRHGNLFITLFALMLTAGLPELTSVKD
IQYLKDSLALGKSEEEALKQFKQKFDEALRESWTTKVNWMAHTVRKDYRS
Drugs and Mode of Action
Drug(s) Buparlisib Drug Info Phase 3 Breast cancer [523929], [542804]
AZD8186 Drug Info Phase 1 Solid tumours [524336], [543183]
BAY 1082439 Drug Info Phase 1 Cancer [524125]
CH-5132799 Drug Info Phase 1 Solid tumours [531469], [542708]
GSK2636771 Drug Info Phase 1 Solid tumours [523668], [542883]
INK-1117 Drug Info Phase 1 Solid tumours [549296]
PQR309 Drug Info Phase 1 Pain [543099]
AZD6482 Drug Info Terminated Thrombosis [532011], [542946]
Modulator AZD6482 Drug Info [532011]
BAY 1082439 Drug Info [1572591]
Inhibitor AZD8186 Drug Info [550501]
Buparlisib Drug Info [537633]
CH-5132799 Drug Info [531469]
GSK2636771 Drug Info [542883]
INK-1117 Drug Info [543560]
KU-0060648 Drug Info [532428]
PI-3065 Drug Info [532839]
PIK-75 Drug Info [528931]
PP121 Drug Info [529744]
PQR309 Drug Info [543560]
TGX-221 Drug Info [527515]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
DRM DRM Info
Pathways
BioCyc Pathway Superpathway of inositol phosphate compounds
3-phosphoinositide biosynthesis
KEGG Pathway Inositol phosphate metabolism
ErbB signaling pathway
Ras signaling pathway
Rap1 signaling pathway
cGMP-PKG signaling pathway
cAMP signaling pathway
Chemokine signaling pathway
HIF-1 signaling pathway
FoxO signaling pathway
Phosphatidylinositol signaling system
Sphingolipid signaling pathway
mTOR signaling pathway
PI3K-Akt signaling pathway
AMPK signaling pathway
Apoptosis
Adrenergic signaling in cardiomyocytes
VEGF signaling pathway
Osteoclast differentiation
Focal adhesion
Signaling pathways regulating pluripotency of stem cells
Platelet activation
Toll-like receptor signaling pathway
Jak-STAT signaling pathway
Natural killer cell mediated cytotoxicity
T cell receptor signaling pathway
B cell receptor signaling pathway
Fc epsilon RI signaling pathway
Fc gamma R-mediated phagocytosis
TNF signaling pathway
Leukocyte transendothelial migration
Neurotrophin signaling pathway
Cholinergic synapse
Inflammatory mediator regulation of TRP channels
Regulation of actin cytoskeleton
Insulin signaling pathway
Progesterone-mediated oocyte maturation
Estrogen signaling pathway
Prolactin signaling pathway
Thyroid hormone signaling pathway
Oxytocin signaling pathway
Regulation of lipolysis in adipocytes
Type II diabetes mellitus
Non-alcoholic fatty liver disease (NAFLD)
Aldosterone-regulated sodium reabsorption
Carbohydrate digestion and absorption
Bacterial invasion of epithelial cells
Chagas disease (American trypanosomiasis)
Toxoplasmosis
Amoebiasis
Hepatitis C
Hepatitis B
Measles
Influenza A
HTLV-I infection
Epstein-Barr virus infection
Pathways in cancer
Viral carcinogenesis
Proteoglycans in cancer
Colorectal cancer
Renal cell carcinoma
Pancreatic cancer
Endometrial cancer
Glioma
Prostate cancer
Melanoma
Chronic myeloid leukemia
Acute myeloid leukemia
Small cell lung cancer
Non-small cell lung cancer
Central carbon metabolism in cancer
Choline metabolism in cancer
PANTHER Pathway Angiogenesis
Apoptosis signaling pathway
Axon guidance mediated by netrin
B cell activation
EGF receptor signaling pathway
Endothelin signaling pathway
FGF signaling pathway
Hypoxia response via HIF activation
Inflammation mediated by chemokine and cytokine signaling pathway
Insulin/IGF pathway-protein kinase B signaling cascade
Integrin signalling pathway
Interleukin signaling pathway
PDGF signaling pathway
PI3 kinase pathway
T cell activation
VEGF signaling pathway
p53 pathway
Ras Pathway
p53 pathway feedback loops 2
CCKR signaling map ST
Pathway Interaction Database ErbB4 signaling events
LPA receptor mediated events
TRAIL signaling pathway
Signaling events mediated by TCPTP
FAS (CD95) signaling pathway
CXCR4-mediated signaling events
EGF receptor (ErbB1) signaling pathway
Class I PI3K signaling events
ErbB1 downstream signaling
ErbB2/ErbB3 signaling events
PDGFR-beta signaling pathway
Nephrin/Neph1 signaling in the kidney podocyte
Internalization of ErbB1
CXCR3-mediated signaling events
Reactome PI3K Cascade
GPVI-mediated activation cascade
PIP3 activates AKT signaling
PI3K/AKT activation
Role of phospholipids in phagocytosis
Tie2 Signaling
Constitutive Signaling by Aberrant PI3K in Cancer
DAP12 signaling
Role of LAT2/NTAL/LAB on calcium mobilization
Nephrin interactions
gamma signalling through PI3Kgamma
VEGFA-VEGFR2 Pathway
Interleukin-3, 5 and GM-CSF signaling
Interleukin receptor SHC signaling
Regulation of signaling by CBL
WikiPathways Toll-like receptor signaling pathway
DNA Damage Response (only ATM dependent)
G13 Signaling Pathway
Regulation of Actin Cytoskeleton
Insulin Signaling
Fc epsilon receptor (FCERI) signaling
PI Metabolism
Interleukin-2 signaling
Fcgamma receptor (FCGR) dependent phagocytosis
DAP12 interactions
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)
PIP3 activates AKT signaling
Signaling Pathways in Glioblastoma
TCR signaling
Signaling by PDGF
Signaling by Insulin receptor
NGF signalling via TRKA from the plasma membrane
Nephrin interactions
Interleukin-3, 5 and GM-CSF signaling
GPVI-mediated activation cascade
Cell surface interactions at the vascular wall
MicroRNAs in cardiomyocyte hypertrophy
Regulation of toll-like receptor signaling pathway
AMPK Signaling
References
Ref 523668ClinicalTrials.gov (NCT01458067) A Phase I/IIa, First Time in Human, Study of GSK2636771 in Subjects With Advanced Solid Tumors With Phosphatase and Tensin Homolog (PTEN) Deficiency. U.S. National Institutes of Health.
Ref 523929ClinicalTrials.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 524125ClinicalTrials.gov (NCT01728311) Open Label Study of BAY1082439 in Patients With Advanced Cancer. U.S. National Institutes of Health.
Ref 524336ClinicalTrials.gov (NCT01884285) AZD8186 First Time In Patient Ascending Dose Study. U.S. National Institutes of Health.
Ref 531469The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011 May 15;17(10):3272-81.
Ref 532011Human target validation of phosphoinositide 3-kinase (PI3K)beta: effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kbeta inhibitor. J Thromb Haemost. 2012 Oct;10(10):2127-36.
Ref 542708(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: 7743).
Ref 542804(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 542883(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: 7967).
Ref 542946(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: 8059).
Ref 543099(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: 8383).
Ref 543183(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: 8527).
Ref 549296Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034842)
Ref
Ref 527515PI 3-kinase p110beta: a new target for antithrombotic therapy. Nat Med. 2005 May;11(5):507-14. Epub 2005 Apr 17.
Ref 528931Bioorg Med Chem. 2007 Sep 1;15(17):5837-44. Epub 2007 Jun 6.Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110alpha inhibitors.
Ref 529744Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol. 2008 Nov;4(11):691-9.
Ref 531469The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011 May 15;17(10):3272-81.
Ref 532011Human target validation of phosphoinositide 3-kinase (PI3K)beta: effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kbeta inhibitor. J Thromb Haemost. 2012 Oct;10(10):2127-36.
Ref 5324281-substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones endowed with dual DNA-PK/PI3-K inhibitory activity. J Med Chem. 2013 Aug 22;56(16):6386-401.
Ref 532839Inactivation of PI(3)K p110delta breaks regulatory T-cell-mediated immune tolerance to cancer. Nature. 2014 Jun 19;510(7505):407-11.
Ref 537633Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009 Aug;8(8):627-44.
Ref 542883(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: 7967).
Ref 543560(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. (Target id: 2154).
Ref 550501National Cancer Institute Drug Dictionary (drug id 751594).
Ref 1572591Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

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