Discovery of 12O-A Novel Oral Multi-Kinase Inhibitor for the Treatment of Solid Tumor.

A novel series of pyrimidine-benzotriazole derivatives have been synthesized and evaluated for their anticancer activity against human solid tumor cell lines. The most promising molecule was identified for its excellent antiproliferative activities, especially against the SiHa cell line with IC value as 0.009 μM. Kinase inhibition assay assessed was a potential multi-kinase inhibitor, which possessed potent inhibitory activities against cyclin-dependent kinases (CDKs) and fms-like tyrosine kinase (FLT) with IC values in the nanomolar range. Molecular docking studies illustrated that the introduction of triazole moiety in was critical for CDKs inhibition. In addition, inhibited cancer cell proliferation, colony-formation, and cell cycle progression and provoked apoptotic death in vitro. In an SiHa xenograft mouse model, a once-daily dose of compound at 20 mg/kg significantly suppressed the tumor growth without obvious toxicity. Taken together, provided valuable guide for further structural optimization for CDKs and FLT inhibitors.