Structure-Activity and Structure-Degradation Relationship Studies of 2-Amino-6-(benzimidazol-2-ylmethyl)-N9-heteroarylpurines as Potent and Selective CDK12/13 Inhibitors and Cyclin K Degraders.

Targeted modulation of the CDK12/CycK complex offers a compelling avenue for exploiting transcriptional addiction in cancer. Among emerging strategies, small molecule CDK12/13 inhibitors that induce selective CycK degradation via proximity-based mechanisms are demonstrating encouraging preclinical results. However, the rational design of molecular glue degraders remains challenging as the structural principles governing efficient target degradation are not always well understood. Here, we report the design, synthesis, structure-activity, and structure-degradation relationship studies of a series of highly potent and selective N9-heteroaryl purine-based CDK12/13 inhibitors, and its optimized analog , that act as molecular glue degraders of CycK. In vitro target engagement and in vivo PK/PD studies in mice demonstrate dose-dependent CycK degradation that closely tracks systemic compound exposure. These findings establish CycK as a suitable proximal PD biomarker for this inhibitor class and highlight purine-based scaffolds as a rational framework for the development of bifunctional CDK12/CycK inhibitors and degraders.

PMID: 41533987