Rational Design of Oxazolonylflavone Derivatives as Novel CDK4/9 Inhibitors with Potent Antitumor Efficacy and Oral Bioavailability.

CDK4 and CDK9 are key kinases governing cell cycle progression and transcriptional regulation, respectively. Accumulating evidence supports the therapeutic potential of their concurrent inhibition in oncology. Screening of our in-house natural product library identified kushenmin K, a flavonoid with modest CDK inhibitory and antiproliferative activities. A strategy combining scaffold hopping with structure-guided design yielded HS-36, a novel oxazolylflavone derivative, which potently inhibited both CDK4 (IC50 = 18.9 nM) and CDK9 (IC50 = 4.2 nM). This dual activity effectively blocked cell cycle progression and triggered apoptosis by downregulating key downstream effectors, translating into potent antiproliferative activity. Notably, it maintained this potent activity even in CDK4/6 inhibitor-resistant cell models. Furthermore, HS-36 possessed an excellent pharmacokinetic profile, including good oral bioavailability (F = 41.8%), which enabled solid and well-tolerated in vivo antitumor efficacy (TGI = 68.8%) in a MV-4-11 xenograft model. This work not only presents HS-36 as a promising lead compound but also validates our rational approach to optimizing natural product scaffolds.