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.

细胞周期蛋白依赖性激酶4（CDK4）与细胞周期蛋白依赖性激酶9（CDK9）分别为调控细胞周期进程与转录调控的关键激酶。越来越多的研究证据表明，同时抑制这两种激酶在肿瘤治疗领域具有潜在应用价值。本研究通过内部天然产物库筛选，发现了苦参素K（kushenmin K）——一种具有中等强度CDK抑制活性与抗增殖活性的黄酮类化合物。本研究采用骨架跃迁结合结构导向设计的策略，得到了新型恶唑基黄酮衍生物HS-36，其可强效抑制CDK4（半数抑制浓度IC50=18.9 nM）与CDK9（半数抑制浓度IC50=4.2 nM）。这种双重抑制活性可通过下调关键下游效应分子，有效阻断细胞周期进程并诱导细胞凋亡，进而展现出强效的抗增殖活性。值得注意的是，即便在CDK4/6抑制剂耐药的细胞模型中，该化合物仍可维持其强效活性。此外，HS-36具备优异的药代动力学特征，包括良好的口服生物利用度（F=41.8%），这使其在MV-4-11异种移植模型中展现出稳定且耐受性良好的体内抗肿瘤药效（肿瘤生长抑制率Tumor Growth Inhibition, TGI=68.8%）。本研究不仅将HS-36开发为极具潜力的先导化合物，同时也验证了我们通过理性设计优化天然产物骨架的策略可行性。