Discovery of <b>DN1679</b> 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 <b>DN1679</b>. 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. <b>DN1679</b> possesses promising oral pharmacokinetic properties and, as a monotherapy, effectively suppresses tumor growth in a TNBC xenograft model. Notably, <b>DN1679</b> demonstrates robust synergy with the PARP inhibitor olaparib <i>in vivo</i>, leading to significantly enhanced antitumor efficacy. The optimized pharmacological profile of <b>DN1679</b> and its demonstrated synergistic activity establish it as a compelling therapeutic candidate for the treatment of TNBC.