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.