Discovery of Pyrazolo[1,5- a ]-1,3,5-Triazine Derivatives as Potent, Highly Selective and Orally Available Macrocyclic CDK7 Inhibitors
Quanpeng Wei, Yanxin Tao, Xinpeng Ning, Suyun Jia, Yan Chen, Xiaoli Du, Xinyu Sun, Lingrui Xu, Xinrui Jiang, Pengpeng Niu, Mengyang Fan, Yupeng Li, Dawei Ma, Shan Li, Ke DingAbstract
Cyclin-dependent kinase 7 (CDK7) is a promising cancer therapeutic target due to its dual role in cell cycle progression and gene transcription. However, current CDK7 inhibitors generally exhibit poor kinase selectivity. Herein, we performed in-depth structural optimization on a 17-membered macrocyclic scaffold, and identified compound I-23, which potently inhibits CDK7 with an IC50 value of 3 nM and exhibits exceptional CDK7 selectivity with no significant off-target activity across 416 kinases. I-23 also potently inhibits cell proliferation across a panel of tumor cell lines, induces cell cycle arrest and transcriptional suppression, and downregulates oncoprotein c-Myc, particularly in triple-negative breast cancer cells. Importantly, I-23 shows favorable oral bioavailability (up to 28%) with linear pharmacokinetics. Collectively, this work provides a highly selective and orally bioavailable macrocyclic CDK7 inhibitor, which can serve as a valuable chemical tool for dissecting CDK7 biological functions and a promising lead compound for CDK7-based anticancer drug discovery.