Design, synthesis, and anti-colorectal cancer activity of quinoxalines with improved drug-like properties.

Colorectal cancer (CRC) is strongly associated with aberrant activation of the PI3K/Akt/mTOR pathway, in which PI3Kα represents a clinically validated therapeutic target. Herein, we report the rational design, synthesis, and biological evaluation of quinoxaline derivatives as potent PI3Kα selective inhibitors derived from the lead compound 18a, which was developed in our previous study and suffered from poor drug-like properties. Structure-guided modification led to the identification of compound 8b, which exhibited remarkably improved solubility and oral bioavailability, and it showed nano-mol level inhibitory activity against PI3Kα. In HCT-116 cells, 8b effectively suppressed proliferation, migration, and colony formation, induced apoptosis, and selectively triggered G2/M-phase arrest via downregulation of Cyclin B1 and CDK1.

Mechanistic studies further confirmed robust inhibition of PI3K/Akt/mTOR signaling pathway and associated transcriptional reprogramming. Collectively, 8b represents a promising orally active PI3Kα inhibitor for CRC targeted therapy.