Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: PI3-kinase gamma (PIK3CG)
• Synonyms: p120-PI3K; p110gamma; Serine/threonine protein kinase PIK3CG; PtdIns-3-kinase subunit p110-gamma; PtdIns-3-kinase subunit gamma; PtdIns-3-kinase p110; Phosphoinositol-3 kinase; Phosphoinositide-3-kinase catalytic gamma polypeptide; Phosphoinositide 3-Kinase gamma; Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, gamma isoform; Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform; Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma; PI3Kgamma; PI3K-gamma; PI3K; PI3-kinase subunit gamma; PI3-kinase p110 subunit gamma
• Gene Name: PIK3CG
• DTT Type: Successful target; [1]
• BioChemical Class: Kinase
• UniProt ID: PK3CG_HUMAN
• TTD ID: T95913
• EC Number: EC 2.7.1.153
• Sequence:
  MELENYKQPVVLREDNCRRRRRMKPRSAAASLSSMELIPIEFVLPTSQRKCKSPETALLH
  VAGHGNVEQMKAQVWLRALETSVAADFYHRLGPHHFLLLYQKKGQWYEIYDKYQVVQTLD
  CLRYWKATHRSPGQIHLVQRHPPSEESQAFQRQLTALIGYDVTDVSNVHDDELEFTRRGL
  VTPRMAEVASRDPKLYAMHPWVTSKPLPEYLWKKIANNCIFIVIHRSTTSQTIKVSPDDT
  PGAILQSFFTKMAKKKSLMDIPESQSEQDFVLRVCGRDEYLVGETPIKNFQWVRHCLKNG
  EEIHVVLDTPPDPALDEVRKEEWPLVDDCTGVTGYHEQLTIHGKDHESVFTVSLWDCDRK
  FRVKIRGIDIPVLPRNTDLTVFVEANIQHGQQVLCQRRTSPKPFTEEVLWNVWLEFSIKI
  KDLPKGALLNLQIYCGKAPALSSKASAESPSSESKGKVQLLYYVNLLLIDHRFLLRRGEY
  VLHMWQISGKGEDQGSFNADKLTSATNPDKENSMSISILLDNYCHPIALPKHQPTPDPEG
  DRVRAEMPNQLRKQLEAIIATDPLNPLTAEDKELLWHFRYESLKHPKAYPKLFSSVKWGQ
  QEIVAKTYQLLARREVWDQSALDVGLTMQLLDCNFSDENVRAIAVQKLESLEDDDVLHYL
  LQLVQAVKFEPYHDSALARFLLKRGLRNKRIGHFLFWFLRSEIAQSRHYQQRFAVILEAY
  LRGCGTAMLHDFTQQVQVIEMLQKVTLDIKSLSAEKYDVSSQVISQLKQKLENLQNSQLP
  ESFRVPYDPGLKAGALAIEKCKVMASKKKPLWLEFKCADPTALSNETIGIIFKHGDDLRQ
  DMLILQILRIMESIWETESLDLCLLPYGCISTGDKIGMIEIVKDATTIAKIQQSTVGNTG
  AFKDEVLNHWLKEKSPTEEKFQAAVERFVYSCAGYCVATFVLGIGDRHNDNIMITETGNL
  FHIDFGHILGNYKSFLGINKERVPFVLTPDFLFVMGTSGKKTSPHFQKFQDICVKAYLAL
  RHHTNLLIILFSMMLMTGMPQLTSKEDIEYIRDALTVGKNEEDAKKYFLDQIEVCRDKGW
  TVQFNWFLHLVLGIKQGEKHSA
• Function: Phosphoinositide-3-kinase (PI3K) that phosphorylates 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. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to GRK2 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis.
• 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)
  MicroRNAs in cancer (hsa05206)
  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)
  Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants (R-HSA-1236382)
  PI3K events in ERBB4 signaling (R-HSA-1250342)
  PIP3 activates AKT signaling (R-HSA-1257604)
  GAB1 signalosome (R-HSA-180292)
  PI3K events in ERBB2 signaling (R-HSA-1963642)
  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)
  Costimulation by the CD28 family (R-HSA-388841)
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)
  G beta (R-HSA-392451)
  G alpha (q) signalling events (R-HSA-416476)
  G alpha (12/13) signalling events (R-HSA-416482)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  Interleukin-3, 5 and GM-CSF signaling (R-HSA-512988)
  Constitutive Signaling by EGFRvIII (R-HSA-5637810)
  PI-3K cascade (R-HSA-5654689)
  PI-3K cascade (R-HSA-5654695)
  PI-3K cascade (R-HSA-5654710)
  PI-3K cascade (R-HSA-5654720)
  Interleukin receptor SHC signaling (R-HSA-912526)
  Regulation of signaling by CBL (R-HSA-912631)
  PI3K Cascade (R-HSA-109704)
• BioCyc Pathway: MetaCyc:HS02818-MON

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BAY 80-6946	DMLOS5R	Follicular lymphoma	2A80	Approved	[2]
IPI-145	DMWA24P	Follicular lymphoma	2A80	Approved	[1]

35 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	[3]
Enzastaurin	DM5H0R9	Diffuse large B-cell lymphoma	2A81	Phase 3	[4]
GDC-0032	DMT4QHD	Breast cancer	2C60-2C65	Phase 3	[4]
Rigosertib	DMOSTXF	Myelodysplastic syndrome	2A37	Phase 3	[5]
AZD8154	DMK13L1	Asthma	CA23	Phase 2	[6]
BEZ235	DMKBRDL	Solid tumour/cancer	2A00-2F9Z	Phase 2	[7]
CLR-1404	DMAW4EL	Solid tumour/cancer	2A00-2F9Z	Phase 2	[8]
GDC-0077	DMY6WUV	Solid tumour/cancer	2A00-2F9Z	Phase 2	[4]
GDC-0084	DMA9SEY	Glioblastoma of brain	2A00.00	Phase 2	[9]
GDC-0980/RG7422	DMF3MV1	Non-hodgkin lymphoma	2B33.5	Phase 2	[10]
GDC0941	DM1YAK6	Breast cancer	2C60-2C65	Phase 2	[3]
IPI-549	DMG5Q7F	Bladder cancer	2C94	Phase 2	[4]
PF-04691502	DMS610L	Endometrial cancer	2C76	Phase 2	[11]
PF-05212384	DMBL3VD	Solid tumour/cancer	2A00-2F9Z	Phase 2	[12]
PQR309	DMMCYZ8	Squamous head and neck cell carcinom	2D60.0	Phase 2	[8]
PX-866	DMYISJK	Solid tumour/cancer	2A00-2F9Z	Phase 2	[3]
SAR245409	DMQM7IL	Solid tumour/cancer	2A00-2F9Z	Phase 2	[13]
SF1126	DML10K3	Head and neck cancer	2D42	Phase 2	[14]
XL147	DMML7BE	Solid tumour/cancer	2A00-2F9Z	Phase 2	[13]
BGT226	DMXKDUL	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[15]
CLR-1401	DM2FSM5	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[8]
CLR457	DM64FY7	Advanced solid tumour	2A00-2F9Z	Phase 1/2	[16]
CUDC-907	DMHIQDC	Acute myelogenous leukaemia	2A41	Phase 1/2	[17]
PA-799	DMLSYJQ	Colorectal cancer	2B91.Z	Phase 1/2	[18]
TG100-115	DMON4IL	Angioedema	4A00.15	Phase 1/2	[19]
ZX-101A	DM65AV2	Chronic lymphocytic leukaemia	2A82.0	Phase 1/2	[20]
AZD8186	DMWYF1H	Solid tumour/cancer	2A00-2F9Z	Phase 1	[4]
DS-7423	DMCFJM3	Solid tumour/cancer	2A00-2F9Z	Phase 1	[21]
GSK2126458	DMM7ZXR	Lymphoma	2A80-2A86	Phase 1	[22]
KA2237	DMFKEVO	B-cell lymphoma	2A86	Phase 1	[4]
LY294002	DMY1AFS	Neuroblastoma	2D11.2	Phase 1	[23]
P-7170	DMIYQEM	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
Perifosine	DMVYRH2	Solid tumour/cancer	2A00-2F9Z	Phase 1	[24]
VS-5584	DMMO3G5	Malignant mesothelioma	2C26.0	Phase 1	[25]
ZSTK474	DMVIMQX	Solid tumour/cancer	2A00-2F9Z	Phase 1	[26]

5 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Adyvia	DMZ7WKN	Type-2 diabetes	5A11	Discontinued in Phase 2	[27]
GSK1059615	DMI6KQM	Breast cancer	2C60-2C65	Discontinued in Phase 1	[3]
PX-867	DMCNE2G	Cardiovascular disease	BA00-BE2Z	Terminated	[28]
SCR-44001	DMFZNUA	Solid tumour/cancer	2A00-2F9Z	Terminated	[29]
Wortmannin	DM8EVK5	Haematological malignancy	2B33.Y	Terminated	[30]

27 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol	DM54MDH	Discovery agent	N.A.	Investigative	[31]
5-QUINOXALIN-6-YLMETHYLENE-THIAZOLIDINE-2,4-DIONE	DMVX063	Discovery agent	N.A.	Investigative	[32]
AEZS-126	DMM52FD	Solid tumour/cancer	2A00-2F9Z	Investigative	[8]
AS-604850	DM9IUSM	Discovery agent	N.A.	Investigative	[33]
BAG956	DMWC34B	Haematological malignancy	2B33.Y	Investigative	[34]
CU-906	DMY1WEM	Solid tumour/cancer	2A00-2F9Z	Investigative	[8]
CZC 24832	DMLBYFG	Discovery agent	N.A.	Investigative	[35]
CZC-19091	DMYBL5G	Inflammation	1A00-CA43.1	Investigative	[13]
Ethyl 1-[(1H-benzimidazol-2(3H)one-5-yl)sulfonyl]-1H-pyrrole-2-carboxylate	DM3FH02	Discovery agent	N.A.	Investigative	[36]
Her2- and PSA-targeted TGX-D1	DM0VC84	Prostate cancer	2C82.0	Investigative	[37]
HM-5016699	DMKHVUE	Solid tumour/cancer	2A00-2F9Z	Investigative	[8]
HS-173	DM0A2UF	Discovery agent	N.A.	Investigative	[38]
KU-0060648	DMQWS6U	Discovery agent	N.A.	Investigative	[39]
LOR-220	DM71BIC	Bacterial infection	1A00-1C4Z	Investigative	[8]
LY-292223	DML36ZE	Discovery agent	N.A.	Investigative	[36]
Multiform PI3K inhibitors	DMW2Z4I	Inflammation	1A00-CA43.1	Investigative	[8]
Myricetin	DMTV4L0	Discovery agent	N.A.	Investigative	[40]
P-6915	DMJDI7O	Solid tumour/cancer	2A00-2F9Z	Investigative	[8]
PF-03772304	DMJ0936	Solid tumour/cancer	2A00-2F9Z	Investigative	[41]
PF-4989216	DMSG6F1	Solid tumour/cancer	2A00-2F9Z	Investigative	[8]
PI-103	DMEK4TJ	Haematological malignancy	2B33.Y	Investigative	[34]
PI-3065	DMCQUWI	Discovery agent	N.A.	Investigative	[42]
PIK-75	DM9BQTX	Discovery agent	N.A.	Investigative	[31]
PKI-402	DM6NX4H	Solid tumour/cancer	2A00-2F9Z	Investigative	[43]
PP121	DMU8KTO	Discovery agent	N.A.	Investigative	[44]
TGX-221	DMM0LRE	Discovery agent	N.A.	Investigative	[45]
WX-037	DM6J7OQ	Solid tumour/cancer	2A00-2F9Z	Investigative	[8]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	1.67E-01	0.25	0.73
Breast cancer	2C82	Breast tissue	1.16E-01	-0.17	-0.49
Uterine cancer	2C82	Endometrium tissue	9.64E-01	-0.07	-0.3
Type 2 diabetes	5A11	Liver tissue	1.98E-01	-0.05	-0.55
Multiple myeloma	2C82	Bone marrow	2.69E-02	0.17	0.58

References

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• [2] BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110 and p110 activities in tumor cell lines and xenograft models.Mol Cancer Ther.2013 Nov;12(11):2319-30.
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