Journal Article
Identification of methyl (5-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (CYH33) as an orally bioavailable, highly potent, PI3K alpha inhibitor for the treatment of advanced solid tumors
Xiang, HY; Wang, X; Chen, YH; Zhang, X; Tan, C; Wang, Y; Su, Y; Gao, ZW; Chen, XY; Xiong, B; Gao, ZB; Chen, Y; Ding, J; Meng, LH; Yang, CH; ,
European Journal of Medicinal Chemistry
ISSN: 0223-5234
EISSN: 1768-3254
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
ISSY-LES-MOULINEAUX
In various human cancers, PI3Ks pathway is ubiquitously dysregulated and thus become a promising anti-cancer target. To discover new potent and selective PI3K inhibitors as potential anticancer drugs, new pyrrolo[2,1-f][1,2,4]triazines were designed, leading to the discovery of compound 37 (CYH33), a selective PI3Kα inhibitor (IC50 = 5.9 nM, β/α, δ/α,γ/α = 101-, 13-, 38-fold). Western blot analysis confirmed that compound 37 could inhibit phosphorylation of AKT in human cancer cells to modulate the cellular PI3K/AKT/mTOR pathway. And further evaluation in vivo against SKOV-3 xenograft models demonstrated that a dose-dependent antitumor efficacy was achieved.
Anti-cancer; PI3K; Pyrrolo[2,1-f][1,2,4]triazine; Target therapy; antineoplastic agent; carbamic acid derivative; cyh 33; mammalian target of rapamycin; methyl [5 [6 [[4 (methylsulfonyl)piperazin 1 yl]methyl] 4 morpholinopyrrolo[2,1 f][1,2,4][triazin 2yl] 4 (trifluorometyl)pyridin 2 yl]carbamate; phosphatidylinositol 3 kinase inhibitor; pictilisib; protein kinase B; unclassified drug; advanced cancer; Akt/mTOR signaling; animal cell; animal experiment; animal model; Article; cancer cell; comparative effectiveness; controlled study; dose response; drug cytotoxicity; drug design; drug efficacy; drug mechanism; drug potency; drug screening; female; human; human cell; IC50; in vivo study; male; molecular model; mouse; nonhuman; pharmacodynamics; Pi3K/Akt signaling; protein phosphorylation; rat; signal transduction; SK-OV-3 cell line; solid malignant neoplasm; tumor xenograft; Western blotting
