European Journal of Medicinal Chemistry p. 731 - 743 (2016)
Update date:2022-08-18
Topics:
Yadav, Rammohan R.
Guru, Santosh K.
Joshi, Prashant
Mahajan, Girish
Mintoo, Mubashir J.
Kumar, Vikas
Bharate, Sonali S.
Mondhe, Dilip M.
Vishwakarma, Ram A.
Bhushan, Shashi
Bharate, Sandip B.
Isoform-selective inhibition of PI3K-α has been identified as one of the important strategy to discover effective and safer anticancer agents. Herein, we report discovery of ‘quinazoline’ as a new chemotype for isoform-selective PI3K-α inhibitors. The indolyl substituted quinazoline 9u displayed selective inhibition of PI3K-α with IC50value of 0.201?μM with >49.7 over PI3K-β, and δ-isoforms. Quinazoline 9u also inhibited PI3K-γ with IC50value of 0.750 μM (3.7 fold selective for α-versus γ-isoform). The isoform-selective inhibition was also demonstrated at protein-expression level by western-blot analysis in MCF-7 and PC-3?cells. The isoform-selective inhibitor 9u also showed inhibition of phospho-Akt levels in these cells. Quinazoline 9u showed in-vitro cytotoxicity in MCF-7?cells with GI50of 7?μM, which was highly selective for cancer cells, as it was non-toxic to normal cells fR2, HEK293 and hGF (GI50?>?50?μM). Compound 9u at 25?mg/kg dose showed 62 and 37% TGI in Ehrlich Ascites Carcinoma and Ehrlich Solid Tumor mice models. In nutshell, our efforts to identify potent and efficacious PI3K inhibitors resulted in the discovery of a new class of isoform-selective PI3K-α inhibitors possessing promising in-vivo anticancer activity.
View MoreHubei Lingsheng Pharmaceuticals Co., Ltd.
Contact:+86-0710-3538058
Address:Xiangyang City Xiangcheng Economic Development Zone, Hubei Province
Hangzhou Yingshanhua Pigment Chemicals Co.,Ltd.
Contact:+86-0150-58101658
Address:Nanyang Economic DevelopmentZong,Xiaoshan,Hangzhou,China
LIAOYANG TENGYUAN FOOD ADDITIVE FACTORY
Contact:+86-419-5807666
Address:Haodianzi village,Hanling Town,Liaoyang county
Hubei Onward Bio-Development Co., Ltd.
Contact:+86-718-8417012
Address:No.517,Shizhou Avenue,Enshi City,Hubei Province,China,445002
Hubei Lingsheng Pharmaceuticals Co., Ltd.
Contact:+86-0710-3538058
Address:Xiangyang City Xiangcheng Economic Development Zone, Hubei Province
Doi:10.1016/S0040-4039(01)90798-1
(1963)Doi:10.1021/jo00907a037
(1975)Doi:10.1016/S0040-4020(01)90473-9
(1994)Doi:10.1039/b209344h
(2002)Doi:10.1002/jhet.5570350318
(1998)Doi:10.1016/S0040-4039(00)01843-8
(2000)