| Target Validation Information | |||||
|---|---|---|---|---|---|
| TTD ID | T95913 | ||||
| Target Name | PI3-kinase gamma (PIK3CG) | ||||
| Type of Target |
Successful |
||||
| Drug Potency against Target | GDC0941 | Drug Info | IC50 = 3~33 nM | [4] | |
| 3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol | Drug Info | IC50 = 660 nM | [2] | ||
| Ethyl 1-[(1H-benzimidazol-2(3H)one-5-yl)sulfonyl]-1H-pyrrole-2-carboxylate | Drug Info | IC50 = 6000 nM | [1] | ||
| LY-292223 | Drug Info | IC50 = 14000 nM | [1] | ||
| PKI-402 | Drug Info | IC50 = 9.2 nM | [3] | ||
| Action against Disease Model | BEZ235 | Drug Info | The dual PI3K/mTOR inhibitor NVP-BEZ235 was compared with rapamycin in RCC cell lines and xenografts generated from 786-O and A498 cells. Treatment of RCC cell lines with NVP-BEZ235 in vitro resulted in the nuclear translocation of p27, greater reduction in t uMor cell proliferation, and more complete suppression of Akt, Mnk-1, eIF4E, and 4EBP-1 phosphorylation and cyclin D1and hypoxia-inducible factor 2alpha (HIF2alpha) expression than that achieved with rapamycin. The reduction of HIF2alpha levels correlated with reduced HIF activity as determined by luciferase assay.NVP-BEZ235 induced growth arrest in both the 786-O and A498 xenografts that was associated with inhibition of Akt and S6 phosphorylation as well as the induction of apoptosis and reduction in markersof t uMor cell proliferation. In contrast, rapamycin induced only minimal growth retardation. | ||
| References | |||||
| REF 1 | LY294002-geldanamycin heterodimers as selective inhibitors of the PI3K and PI3K-related family. Bioorg Med Chem Lett. 2001 Apr 9;11(7):909-13. | ||||
| REF 2 | 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. | ||||
| REF 3 | Lead optimization of N-3-substituted 7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors: di... J Med Chem. 2010 Jan 28;53(2):798-810. | ||||
| REF 4 | Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol. 2008 Aug;8(4):393-412. | ||||
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