Discovery of 4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxamide derivatives as PI3Kα inhibitors via virtual screening and docking-based structure optimization

Compound 1 with pyrazolo[1,5-a]quinoxalin-4(5H)-one scaffold was identified as a PI3Kα inhibitor hit via virtual screening strategy. Additional similarity search and molecular docking based structural modification yielded a novel series of pyrazolo[1,5-a]quinoxalin-4(5H)-one derivatives. The most potent compound 49b exhibited remarkably improved PI3Kα inhibitory activity with IC50 value of 0.24 μM and moderate to good isoform selectivity over other class I PI3K isoforms. In addition, 49b significantly inhibited the proliferation of Kasumi-1 and T47D cells with IC50 value of 1.64 and 1.82 μM, respectively. Further PK study demonstrated that it has favorable pharmacokinetic profiles (AUC0-t = 3294.05 ng·h/mL at 5.0 mg/kg PO, F = 91.8%). All these data indicated that compound 49b was a promising PI3Kα inhibitor with beneficial drug-like properties and merited further development.