Therapeutic Targets Database
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TTD Target ID: TTDC00140

Target Information
NamePhosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, gamma isoform    
Type of targetClinical trial target    
SynonymsPI3-kinase p110 subunit gamma    
PI3K    
PI3Kgamma    
Phosphoinositide 3-Kinase gamma    
PtdIns-3-kinase p110    
DiseaseAngioedema
[ICD9: 277.6, 995.1   ICD10: D84.1, T78.3]
[1][2][3]
Cancer, unspecific
[ICD9: 140-229   ICD10: C00-C96]
[4][5][6]
Heart failure
[ICD9: 428   ICD10: I50]
[7][8]
Myocardial infarction
[ICD9: 410   ICD10: I21, I22]
[1][2][3]
Solid tumors
[ICD9: 140-199, 210-229   ICD10: C00-C75, C7A, C7B, D10-D36, D3A]
[5][6]
Drug(s)AZD6482Phase IIThrombosis[9]
BAY 80-6946Phase IICancer
BAY 80-6946Phase IINon-Hodgkin lymphoma
GDC-0980/RG7422Phase IINon-Hodgkin lymphoma
PF-04691502Phase IIEndometrial cancer
PF-05212384Phase IIEndometrial cancer
RG7422Phase IISolid tumors, non-Hodgkin's lymphoma
XL147Phase IIEndometrial Cancer[10]
BEZ235Phase I/IIAdvanced solid tumours; Advanced breast cancer[11]
BGT226Phase I/IISolid tumours; Advanced breast cancer; Cowden¡¯s syndrome[11]
BKM120Phase I/IIMetastatic Breast Cancer[11]
TG100-115Phase I/IIAngioedema, Myocardial infarction[1][2][3]
XL765Phase I/IISolid tumours; non-small-cell lung cancer; malignant gliomas[12]
2636771Phase ICancer
AR-12Phase ILymphoma
BAY 1082439Phase ICancer
BYL719Phase ISolid tumors
CAL-101Phase IChronic lymphocytic leukaemia; acute myeloid leukaemia; non-Hodgkin¡¯s lymphoma[11]
CHUPhase ISolid tumors
CUDC-907Phase IDiffuse large B-cell lymphoma (see also myeloma)
CUDC-907Phase IMyeloma (see also lymphoma)
DS-7423Phase ISolid cancer
GDC-0032Phase IMetastatic solid tumors
GDC-0980Phase IAdvanced solid tumours, non-Hodgkin's lymphoma[13]
GDC0941Phase IAdvanced solid tumours; non-Hodgkin¡¯s lymphoma[11][14]
GSK2126458Phase ILymphoma
GSK2126458Phase ISolid Tumors
PF-04691502Phase ISolid Tumors
PF-05212384Phase ISolid Tumors
PX-866Phase IAdvanced solid tumours[11]
SAR245408/MSC1936369B combination therapyPhase ISolid Tumors
SAR245409/MSC1936369B combination therapyPhase ISolid Tumors
SF1126Phase ISolid Tumors[5][6]
GSK1059615Terminated in Phase IAdvanced solid tumours; metastatic breast cancer; endometrial cancer; lymphoma[11]
LY294002Discontinued in Phase ICancer[15]
PI3K alphaDiscontinued in Phase ICancer[16]
BioChemical ClassTransferases transferring phosphorus-containing groups    
EC NumberEC 2.7.1.153
PathwayAcute myeloid leukemia
Apoptosis
B cell receptor signaling pathway
Chemokine signaling pathway
Chronic myeloid leukemia
Colorectal cancer
Endometrial cancer
ErbB signaling pathway
Fc epsilon RI signaling pathway
Focal adhesion
Glioma
Inositol phosphate metabolism
Insulin signaling pathway
Jak-STAT signaling pathway
Leukocyte transendothelial migration
Melanoma
Natural killer cell mediated cytotoxicity
Non-small cell lung cancer
Pancreatic cancer
Pathways in cancer
Phosphatidylinositol signaling system
Prostate cancer
Regulation of actin cytoskeleton
Renal cell carcinoma
Small cell lung cancer
T cell receptor signaling pathway
Toll-like receptor signaling pathway
Type II diabetes mellitus
VEGF signaling pathway
mTOR signaling pathway
UniProt IDP48736
PDB Structure1E8Y; 1E8Z; 1HE8; 2A4Z; 2A5U; 2CHW; 2CHX; 2CHZ; 2V4L; 3APC; 3APD; 3APF; 3CSF; 3CST; 3DBS; 3DPD; 3ENE; 3IBE; 3L08; 3L13; 3L16; 3L17; 3L54; 3LJ3; 3MJW; 3ML8; 3ML9; 3NZS; 3NZU; 3OAW; 3P2B; 3PRE; 3PRZ; 3PS6; 3QAQ; 3QAR; 3QJZ; 3QK0; 3R7Q; 3R7R; 3S2A; 3SD5; 3T8M; 3TJP; 3TL5; 3ZVV; 3ZW3; 4ANU; 4ANV; 4ANW; 4ANX; 4AOF; 4DK5; 4EZJ; 4EZK; 4EZL; 4F1S; 4FA6; 4FAD; 4FHJ; 4FHK; 4FJY; 4FJZ; 4FLH; 4FUL; 4G11; 4GB9; 4HLE.    
Function3-phosphorylates the cellular phosphoinositide ptdins-4,5-biphosphate (ptdins(4,5)p2).    
SequenceMELENYKQPVVLREDNCRRRRRMKPRSAAASLSSMELIPIEFVLPTSQRKCKSPETALLH VAGHGNVEQMKAQVWLRALETSVAADFYHRLGPHHFLLLYQKKGQWYEIYDKYQVVQTLD CLRYWKATHRSPGQIHLVQRHPPSEESQAFQRQLTALIGYDVTDVSNVHDDELEFTRRGL VTPRMAEVASRDPKLYAMHPWVTSKPLPEYLWKKIANNCIFIVIHRSTTSQTIKVSPDDT PGAILQSFFTKMAKKKSLMDIPESQSEQDFVLRVCGRDEYLVGETPIKNFQWVRHCLKNG EEIHVVLDTPPDPALDEVRKEEWPLVDDCTGVTGYHEQLTIHGKDHESVFTVSLWDCDRK FRVKIRGIDIPVLPRNTDLTVFVEANIQHGQQVLCQRRTSPKPFTEEVLWNVWLEFSIKI KDLPKGALLNLQIYCGKAPALSSKASAESPSSESKGKVQLLYYVNLLLIDHRFLLRRGEY VLHMWQISGKGEDQGSFNADKLTSATNPDKENSMSISILLDNYCHPIALPKHQPTPDPEG DRVRAEMPNQLRKQLEAIIATDPLNPLTAEDKELLWHFRYESLKHPKAYPKLFSSVKWGQ QEIVAKTYQLLARREVWDQSALDVGLTMQLLDCNFSDENVRAIAVQKLESLEDDDVLHYL LQLVQAVKFEPYHDSALARFLLKRGLRNKRIGHFLFWFLRSEIAQSRHYQQRFAVILEAY LRGCGTAMLHDFTQQVQVIEMLQKVTLDIKSLSAEKYDVSSQVISQLKQKLENLQNSQLP ESFRVPYDPGLKAGALAIEKCKVMASKKKPLWLEFKCADPTALSNETIGIIFKHGDDLRQ DMLILQILRIMESIWETESLDLCLLPYGCISTGDKIGMIEIVKDATTIAKIQQSTVGNTG AFKDEVLNHWLKEKSPTEEKFQAAVERFVYSCAGYCVATFVLGIGDRHNDNIMITETGNL FHIDFGHILGNYKSFLGINKERVPFVLTPDFLFVMGTSGKKTSPHFQKFQDICVKAYLAL RHHTNLLIILFSMMLMTGMPQLTSKEDIEYIRDALTVGKNEEDAKKYFLDQIEVCRDKGW TVQFNWFLHLVLGIKQGEKHSA
Target ValidationClick to Find Target Validation Information.    
Inhibitor2- (4-Morpholinyl)-8-Phenyl-4h-1-Benzopyran-4-One[17]
3- (4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol[18]
5-QUINOXALIN-6-YLMETHYLENE-THIAZOLIDINE-2,4-DIONE[19]
AZD6482[9]
BAG956[14]
BEZ235[11]
BGT226[11]
BKM120[11]
CAL-101[11]
GDC-0980[13]
GDC0941[11][14]
GSK1059615[11]
LY-292223[20]
LY-293646[20]
LY-294002[18]
LY294002[15]
LY294002[21][22][14]
Myricetin[17]
PI-103[14]
PI3K alpha[16]
PKI-402[23]
PX-866[11]
Quercetin[17]
SF1126[5][6]
Staurosporine[17]
TG100-115[1][2][3]
Wortmannin[21][22][14]
XL147[10]
XL765[12]
ZSTK474[14]
MultitargetBEZ235[11]
BGT226[11]
GDC-0980[13]
XL765[12]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1Aerosolized phosphoinositide 3-kinase gamma/delta inhibitor TG100-115 [3-[2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol] as a therapeutic candidate for asthma and chronic obstructive pulmonary disease. J Pharmacol Exp Ther. 2009 Mar;328(3):758-65. Epub 2008 Dec 4. To Reference
Ref 2Isoform-selective PI3K inhibitors as novel therapeutics for the treatment of acute myocardial infarction. Biochem Soc Trans. 2007 Apr;35(Pt 2):204-6. To Reference
Ref 3PI3Kgamma inhibition: towards an 'aspirin of the 21st century'? Nat Rev Drug Discov. 2006 Nov;5(11):903-18. Epub 2006 Oct 13. To Reference
Ref 4First-in-class, first-in-human phase I results of targeted agents: Highlights of the 2008 American Society of Clinical Oncology meeting. J Hematol Oncol. 2008 Oct 29;1:20. To Reference
Ref 5A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res. 2008 Jan 1;68(1):206-15. To Reference
Ref 6PI3 kinase/AKT pathway as a therapeutic target in multiple myeloma. Future Oncol. 2007 Dec;3(6):639-47. To Reference
Ref 7Phosphoinositide 3-kinase gamma-deficient mice are protected from isoproterenol-induced heart failure. Circulation. 2003 Oct 28;108(17):2147-52. Epub 2003 Sep 8. To Reference
Ref 8Phosphoinositide 3-kinase gamma: kinase-dependent and -independent activities in cardiovascular function and disease. Biochem Soc Trans. 2004 Apr;32(Pt 2):383-6. To Reference
Ref 9AstraZeneca. Product Development Pipeline. January 29 2009. To Reference
Ref 10CenterWatch. Drugs in Clinical Trials Database. CenterWatch. 2008. To Reference
Ref 11Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009 Aug;8(8):627-44. To Reference
Ref 12Pipeline of EXELIXIS. EXELIXIS. 2009 To Reference
Ref 132011 Pipeline of Genentech. To Reference
Ref 14The PI3K/Akt pathway as a target in the treatment of hematologic malignancies. Anticancer Agents Med Chem. 2009 Jun;9(5):550-9. To Reference
Ref 15Genentech. Product Development Pipeline. July 2009. To Reference
Ref 16Roche. Product Development Pipeline. July 29 2009. To Reference
Ref 17Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. To Reference
Ref 18Bioorg 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. To Reference
Ref 19Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. To Reference
Ref 20Bioorg Med Chem Lett. 2001 Apr 9;11(7):909-13.LY294002-geldanamycin heterodimers as selective inhibitors of the PI3K and PI3K-related family. To Reference
Ref 21Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to ionizing radiation. Cancer Res. 2002 Aug 15;62(16):4671-7. To Reference
Ref 22Estrogen regulation of c-fos gene expression through phosphatidylinositol-3-kinase-dependent activation of serum response factor in MCF-7 breast cancer cells. Biochem Biophys Res Commun. 2002 Jun 7;294(2):384-94. To Reference
Ref 23J Med Chem. 2010 Jan 28;53(2):798-810.Lead optimization of N-3-substituted 7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors: discovery of PKI-402. To Reference



 

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Professor in Department of Pharmacy
National University of Singapore, Singapore


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