Cyclin-dependent kinases (CDKs) are critical cell cycle regulators that are often overexpressed in tumors, making them promising targets for anti-cancer therapies. Despite substantial advancements in optimizing the selectivity and drug-like properties of CDK inhibitors, safety of multi-target inhibitors remains a significant challenge. Macrocyclization is a promising drug discovery strategy to improve the pharmacological properties of existing compounds. Here we report the development of a macrocyclization platform that enabled the highly efficient discovery of a novel, macrocyclic CDK2/4/6 inhibitor from an acyclic precursor (NUV422). Using dihedral angle scan and structure-based, computer-aided drug design to select an optimal ring-closing site and linker length for the macrocycle, we identified as a potent new CDK2/4/6 inhibitor with optimized cellular potency and safety profile compared to NUV422. Our platform leverages both experimentally-solved as well as generative chemistry-derived macrocyclic structures and can be deployed to streamline the design of macrocyclic new drugs from acyclic starting compounds, yielding macrocyclic compounds with enhanced potency and improved drug-like properties.

中文翻译：

---

通过高效的大环药物设计平台发现具有改进效力和 DMPK 特性的大环 CDK2/4/6 抑制剂

细胞周期蛋白依赖性激酶（CDK）是关键的细胞周期调节因子，通常在肿瘤中过度表达，使其成为抗癌治疗的有希望的靶点。尽管在优化 CDK 抑制剂的选择性和类药特性方面取得了实质性进展，但多靶点抑制剂的安全性仍然是一个重大挑战。大环化是一种有前景的药物发现策略，可改善现有化合物的药理学特性。在此，我们报告了大环化平台的开发，该平台能够从无环前体 (NUV422) 高效发现新型大环 CDK2/4/6 抑制剂。使用二面角扫描和基于结构的计算机辅助药物设计来选择大环的最佳闭环位点和接头长度，我们确定了一种有效的新型 CDK2/4/6 抑制剂，与同类药物相比，具有优化的细胞效力和安全性。 NUV422。我们的平台利用实验解决的以及生成化学衍生的大环结构，可用于简化无环起始化合物的大环新药的设计，产生具有增强效力和改善的类药特性的大环化合物。