Discovery of Pyrazolo[1,5- a ]-1,3,5-Triazine Derivatives as Potent, Highly Selective and Orally Available Macrocyclic CDK7 Inhibitors

Abstract 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.