Discovery of Novel <i>N</i>‑(5-(Pyridin-3-yl)‑1<i>H</i>‑indazol-3-yl)benzamide Derivatives as Potent Cyclin-Dependent Kinase 7 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease

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.最新研究证据表明，细胞周期蛋白依赖性激酶7（CDK7）是常染色体显性多囊肾病（autosomal dominant polycystic kidney disease, ADPKD）治疗的新型潜在药物靶点。本研究基于结构分析，设计得到了一款具有全新母核骨架的命中化合物3，并通过合理药物设计策略开展后续药物化学研究，以优化CDK7抑制剂的活性与选择性。代表性化合物B2对CDK7具有强效抑制活性，半数抑制浓度（IC50）为4 nM，且对细胞周期蛋白依赖性激酶家族（CDKs）展现出优异的选择性。在体外马-达二氏犬肾囊肿模型中，化合物B2可强效抑制囊肿生长，且相较于THZ1具有更低的细胞毒性。此外，化合物B2在离体胚胎肾囊肿模型与体内ADPKD小鼠模型中，同样可显著抑制肾脏囊肿的进展。上述研究结果表明，化合物B2是一款极具开发潜力的先导化合物，值得进一步深入研究以开发用于ADPKD治疗的新型治疗药物。