Discovery of a Highly Potent and Selective Dual PROTAC Degrader of CDK12 and CDK13.

Selective degradation of the cyclin-dependent kinases 12 and 13 (CDK12/13) presents a novel therapeutic opportunity for triple-negative breast cancer (TNBC), but there is still a lack of dual CDK12/13 degraders. Here, we report the discovery of the first series of highly potent and selective dual CDK12/13 degraders by employing the proteolysis-targeting chimera (PROTAC) technology. The optimal compound effectively degraded CDK12 and CDK13 with DC values of 2.2 and 2.1 nM, respectively, in MDA-MB-231 breast cancer cells. Global proteomic profiling demonstrated the target selectivity of . , suppressed expression of core DNA damage response (DDR) genes in a time- and dose-dependent manner. Further, markedly inhibited proliferation of multiple TNBC cell lines including MFM223, with an IC value of 47 nM. Importantly, displayed a significantly improved antiproliferative activity compared to the structurally similar inhibitor , suggesting the potential advantage of a CDK12/13 degrader for TNBC targeted therapy.