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

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 PI3Ka inhibitor (IC50 = 5.9 nM, beta/alpha, delta/alpha,gamma/alpha= 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. (C) 2020 Elsevier Masson SAS. All rights reserved.

Automated summary

The PI3Ks pathway is commonly dysregulated in human cancers, making it a promising target for anti-cancer drugs. Compound 37 (CYH33) was identified as a selective PI3Ka inhibitor with potential anti-cancer properties, inhibiting phosphorylation of AKT to modulate the PI3K/AKT/mTOR pathway in human cancer cells. Evaluation in vivo against SKOV-3 xenograft models demonstrated dose-dependent antitumor efficacy.