Discovery of a Selective and Potent Inhibitor of Cyclin-Dependent Kinase 12/13 Employing a Noncovalent Mechanism.

Downregulation of DNA damage repair genes has attracted considerable research attention recently due to the success of poly-(ADP-ribose) polymerase inhibitors. Identification of additional targets and therapies that exploit synthetic lethality could greatly benefit cancer patients. Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13), which regulate RNA polymerase II (RNA Pol II) and, therefore, gene transcription, represented promising therapeutic targets. Although several inhibitors for these kinases have been disclosed, few have progressed to the clinic. Most existing inhibitors utilize a covalent warhead to obtain potency and selectivity. In this study, we reported the design and development of a series of highly selective noncovalent inhibitors targeting CDK12 and 13. This campaign led to the identification of a lead compound exhibiting outstanding potency and favorable absorption, distribution, metabolism, and excretion profiles, as well as favorable pharmacokinetic properties, thereby demonstrating significant potential for therapeutic applications.