Design, Synthesis, and Biological Evaluation of Novel Orally Available Covalent CDK12/13 Dual Inhibitors for the Treatment of Tumors

Cyclin-dependent kinases 12 and 13 (CDK12/13) safeguard
genomic
integrity by preferentially regulating gene expression in the DNA
damage response (DDR). The CDK12/13-mediated upregulation of DDR genes
and pathways significantly contributes to both tumorigenesis and the
development of resistance to antitumor therapies. Thus, the functional
inhibition of CDK12/13 offers an attractive strategy to combat carcinogenesis,
particularly for refractory and treatment-resistant cancers. Here,
we report the discovery of compound 12b as a novel, potent,
orally available covalent CDK12/13 dual inhibitor with a promising
safety profile and robust in vivo antitumor properties.