Discovery of CTX-439: A Potent and Selective CDK12 Inhibitor as a Prospective Anti-Cancer Drug.

Cyclin-dependent kinase 12 (CDK12) is a transcription-associated kinase critical in regulating transcription, mRNA splicing, translation, cell cycle progression, and DNA damage repair (DDR) pathways. CDK12 is a notable therapeutic target in cancer owing to its regulation of key DDR genes, including BRCA1 and BRCA2, which are essential in maintaining genomic stability. In this study, we describe the lead optimization of a 1,4-trans-cyclohexane-based series, resulting in the discovery of a novel and highly selective CDK12 inhibitor, CTX-439. CTX-439 demonstrated robust CDK12 inhibition, sustained potency against its homologous protein CDK13, and outstanding selectivity over other CDKs and the broader kinome. A comprehensive in vitro evaluation, including ADME-Tox profiling, identified CTX-439 as a promising drug candidate for targeted cancer therapy.