Discovery of DN1679 as a Potent, Orally Bioavailable, and Highly Selective CDK12/13 Dual Degrader for the Treatment of Triple-Negative Breast Cancer

The dual degradation of cyclin-dependent kinases 12 and 13 (CDK12/13) is a promising therapeutic strategy for triple-negative breast cancer (TNBC), yet identifying clinical candidates with optimized pharmacological profiles remains an ongoing priority. Herein, we describe a rational, structure-based campaign to develop a highly potent and selective degrader. Systematic modification of an initial lead, which showed undesired off-target activity, led to the discovery of DN1679. This degrader potently and selectively removes CDK12/13 (DC50 < 10 nM) and shows a favorable therapeutic window, with high potency against TNBC cells but significantly reduced activity in nonmalignant cell lines. DN1679 possesses promising oral pharmacokinetic properties and, as a monotherapy, effectively suppresses tumor growth in a TNBC xenograft model. Notably, DN1679 demonstrates robust synergy with the PARP inhibitor olaparib in vivo, leading to significantly enhanced antitumor efficacy. The optimized pharmacological profile of DN1679 and its demonstrated synergistic activity establish it as a compelling therapeutic candidate for the treatment of TNBC.