Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTTHBCA)

• DTT Name: PI3-kinase beta (PIK3CB)
• Synonyms: p110beta; PtdIns3kinase subunit p110beta; PtdIns3kinase subunit beta; PtdIns-3-kinase subunit p110-beta; PtdIns-3-kinase subunit beta; Phosphatidylinositol 4,5bisphosphate 3kinase catalytic subunitbeta isoform; Phosphatidylinositol 4,5bisphosphate 3kinase 110 kDa catalyticsubunit beta; Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform; Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit beta; PIK3C1; PI3kinase subunit beta; PI3Kbeta; PI3K-beta; PI3-kinase subunit beta
• Gene Name: PIK3CB
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: PK3CB_HUMAN
• TTD ID: T05031
• 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
• 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 receptor tyrosine 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 in the early stage of autophagosome formation. Modulates the intracellular level of PtdIns3P (Phosphatidylinositol 3-phosphate) and activates PIK3C3 kinase activity. May act as a scaffold, independently of 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.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  ErbB signaling pathway (hsa04012)
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  cGMP-PKG signaling pathway (hsa04022)
  cAMP signaling pathway (hsa04024)
  Chemokine signaling pathway (hsa04062)
  HIF-1 signaling pathway (hsa04066)
  FoxO signaling pathway (hsa04068)
  Phosphatidylinositol signaling system (hsa04070)
  Sphingolipid signaling pathway (hsa04071)
  mTOR signaling pathway (hsa04150)
  PI3K-Akt signaling pathway (hsa04151)
  AMPK signaling pathway (hsa04152)
  Apoptosis (hsa04210)
  Adrenergic signaling in cardiomyocytes (hsa04261)
  VEGF signaling pathway (hsa04370)
  Osteoclast differentiation (hsa04380)
  Focal adhesion (hsa04510)
  Signaling pathways regulating pluripotency of stem cells (hsa04550)
  Platelet activation (hsa04611)
  Toll-like receptor signaling pathway (hsa04620)
  Jak-STAT signaling pathway (hsa04630)
  Natural killer cell mediated cytotoxicity (hsa04650)
  T cell receptor signaling pathway (hsa04660)
  B cell receptor signaling pathway (hsa04662)
  Fc epsilon RI signaling pathway (hsa04664)
  Fc gamma R-mediated phagocytosis (hsa04666)
  TNF signaling pathway (hsa04668)
  Leukocyte transendothelial migration (hsa04670)
  Neurotrophin signaling pathway (hsa04722)
  Cholinergic synapse (hsa04725)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Regulation of actin cytoskeleton (hsa04810)
  Insulin signaling pathway (hsa04910)
  Progesterone-mediated oocyte maturation (hsa04914)
  Estrogen signaling pathway (hsa04915)
  Prolactin signaling pathway (hsa04917)
  Thyroid hormone signaling pathway (hsa04919)
  Oxytocin signaling pathway (hsa04921)
  Regulation of lipolysis in adipocytes (hsa04923)
  Type II diabetes mellitus (hsa04930)
  Non-alcoholic fatty liver disease (NAFLD) (hsa04932)
  Aldosterone-regulated sodium reabsorption (hsa04960)
  Carbohydrate digestion and absorption (hsa04973)
  Bacterial invasion of epithelial cells (hsa05100)
  Chagas disease (American trypanosomiasis) (hsa05142)
  Toxoplasmosis (hsa05145)
  Amoebiasis (hsa05146)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Influenza A (hsa05164)
  HTLV-I infection (hsa05166)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
  Proteoglycans in cancer (hsa05205)
  Colorectal cancer (hsa05210)
  Renal cell carcinoma (hsa05211)
  Pancreatic cancer (hsa05212)
  Endometrial cancer (hsa05213)
  Glioma (hsa05214)
  Prostate cancer (hsa05215)
  Melanoma (hsa05218)
  Chronic myeloid leukemia (hsa05220)
  Acute myeloid leukemia (hsa05221)
  Small cell lung cancer (hsa05222)
  Non-small cell lung cancer (hsa05223)
  Central carbon metabolism in cancer (hsa05230)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  GPVI-mediated activation cascade (R-HSA-114604)
  PIP3 activates AKT signaling (R-HSA-1257604)
  PI3K/AKT activation (R-HSA-198203)
  Role of phospholipids in phagocytosis (R-HSA-2029485)
  Tie2 Signaling (R-HSA-210993)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  DAP12 signaling (R-HSA-2424491)
  Role of LAT2/NTAL/LAB on calcium mobilization (R-HSA-2730905)
  Nephrin interactions (R-HSA-373753)
  G beta (R-HSA-392451)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  Interleukin-3, 5 and GM-CSF signaling (R-HSA-512988)
  Interleukin receptor SHC signaling (R-HSA-912526)
  Regulation of signaling by CBL (R-HSA-912631)
  PI3K Cascade (R-HSA-109704)
• BioCyc Pathway: MetaCyc:HS00644-MON

Molecular Interaction Atlas (MIA) of This DTT

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Buparlisib	DM1WEHC	Breast cancer	2C60-2C65	Phase 3	[1]
PQR309	DMMCYZ8	Squamous head and neck cell carcinom	2D60.0	Phase 2	[2]
PA-799	DMLSYJQ	Colorectal cancer	2B91.Z	Phase 1/2	[3]
AZD8186	DMWYF1H	Solid tumour/cancer	2A00-2F9Z	Phase 1	[4]
BAY 1082439	DMLRGX1	Solid tumour/cancer	2A00-2F9Z	Phase 1	[5]
GSK2636771	DMCBGLW	Prostate cancer	2C82.0	Phase 1	[6]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AZD6482	DMVP4E5	Thrombosis	DB61-GB90	Terminated	[7]

5 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
KU-0060648	DMQWS6U	Discovery agent	N.A.	Investigative	[8]
PI-3065	DMCQUWI	Discovery agent	N.A.	Investigative	[9]
PIK-75	DM9BQTX	Discovery agent	N.A.	Investigative	[10]
PP121	DMU8KTO	Discovery agent	N.A.	Investigative	[11]
TGX-221	DMM0LRE	Discovery agent	N.A.	Investigative	[12]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Breast cancer	2C82	Breast tissue	8.82E-15	0.24	0.54

References

• [1] Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009 Aug;8(8):627-44.
• [2] 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. (Target id: 2154).
• [3] The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin Cancer Res. 2011 May 15;17(10):3272-81.
• [4] National Cancer Institute Drug Dictionary (drug id 751594).
• [5] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [6] 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: 7967).
• [7] Human 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.
• [8] 1-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.
• [9] Inactivation of PI(3)K p110delta breaks regulatory T-cell-mediated immune tolerance to cancer. Nature. 2014 Jun 19;510(7505):407-11.
• [10] Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110alpha inhibitors. Bioorg Med Chem. 2007 Sep 1;15(17):5837-44.
• [11] Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol. 2008 Nov;4(11):691-9.
• [12] PI 3-kinase p110beta: a new target for antithrombotic therapy. Nat Med. 2005 May;11(5):507-14.