Alkylsulfonamide-containing quinazoline derivatives as potent and orally bioavailable PI3Ks inhibitors.

ID: ALA4304761

Journal: Bioorg Med Chem

Title: Alkylsulfonamide-containing quinazoline derivatives as potent and orally bioavailable PI3Ks inhibitors.

Authors: Hei YY, Zhang SQ, Feng Y, Wang J, Duan W, Zhang H, Mao S, Sun H, Xin M.

Abstract: Phosphoinositide 3-kinases (PI3Ks) are regarded as promising targets for treatment of various cancers due to their roles in regulating cell proliferation, differentiation, migration, and survival. Here we report our efforts to develop potent and orally bioavailable PI3K inhibitors for the treatment of cancers. The alkylsulfonamide-containing quinazoline derivatives A1-A18 significantly inhibited PI3Kα, and cell proliferation among HCT-116, MCF-7 and SU-DHL-6 cell lines. The optimal compound A1 displayed potent inhibitory activity against PI3Kα (IC₅₀ = 4.5 nM), PI3Kβ (IC₅₀ = 4.5 nM), PI3Kγ (IC₅₀ = 4.5 nM), PI3Kδ (IC₅₀ = 4.5 nM) and significantly inhibited the growth of HCT-116, MCF-7 and SU-DHL-6 cell lines with IC₅₀ values of 0.82 µM, 0.99 µM and 0.19 µM, respectively. Western blot analysis demonstrated A1 significantly suppressed the phosphorylation of AKT^S473 in a dose-dependent manner. Furthermore, A1 could markedly inhibit cancer growth at the dose of 25 mg/kg in nude mouse HCT-116 xenograft model in vivo without causing significant weight loss or toxicity.

CiteXplore: 31176568

DOI: 10.1016/j.bmc.2019.05.043

Patent ID: ┄