Recent evidence suggests that CDK7 is a novel potential drug target for autosomal dominant polycystic kidney disease (ADPKD) treatment. Herein, on the basis of structural analysis, a hit compound 3 with a novel scaffold was designed and subsequent medicinal chemistry efforts by a rational design strategy were conducted to improve CDK7 inhibitors’ potency and selectivity. The representative compound B2 potently inhibited CDK7 with an IC₅₀ value of 4 nM and showed high selectivity over CDKs. Compound B2 showed high potency to inhibit cyst growth and exhibited lower cytotoxicity than THZ1 in an in vitro Madin–Darby canine kidney cyst model. In addition, compound B2 was also highly efficacious in suppressing renal cyst development in an ex vivo embryonic kidney cyst model and in vivo ADPKD mouse model. These results indicate that compound B2 represents a promising lead compound that deserves further investigation to discover novel therapeutic agents for ADPKD.

中文翻译：

---

发现新型 N-(5-(Pyridin-3-yl)-1H-indazol-3-yl)benzamide 衍生物作为有效的细胞周期蛋白依赖性激酶 7 抑制剂，用于治疗常染色体显性多囊肾病

最近的证据表明，CDK7 是常染色体显性多囊肾病 (ADPKD) 治疗的新型潜在药物靶点。在此，在结构分析的基础上，设计了具有新型支架的命中化合物3，并通过合理的设计策略进行了后续的药物化学工作，以提高 CDK7 抑制剂的效力和选择性。代表性化合物B2有效抑制 CDK7，IC ₅₀值为 4 nM，并显示出对 CDK 的高选择性。在体外Madin-Darby 犬肾囊肿模型中，化合物B2显示出抑制囊肿生长的高效力，并且表现出比 THZ1 更低的细胞毒性。此外，化合物B2在体外胚胎肾囊肿模型和体内ADPKD 小鼠模型中抑制肾囊肿发展也非常有效。这些结果表明化合物B2代表了一种有前途的先导化合物，值得进一步研究以发现新的 ADPKD 治疗剂。