2. Academic Validation
  3. 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

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

  • J Med Chem. 2026 Feb 12;69(3):2287-2309. doi: 10.1021/acs.jmedchem.5c02086.
Thiyagamurthy Pandurangan 1,  Solomon Tadesse Zeleke 1,  Anna Iermolaieva 1,  Pompom Ghosh 1,  John Mosior 1,  Luxin Sun 1,  Dylan Grassie 1,  Maximilian Schmitz 2,  Mahalakshmi Naidu Kalaga 1,  William Albritton 1,  Manuel Manzanares Rodas 1,  Sean Chin Chan 1,  Sylvia Frydman 1,  Samer Sansil 3,  Matthias Geyer 2,  Ernst Schönbrunn 1,  William R Roush 4,  Derek R Duckett 1,  Andrii Monastyrskyi 1
Affiliations

Affiliations

  • 1 Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Dr, Tampa, Florida 33612, United States.
  • 2 Institute of Structural Biology, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany.
  • 3 Cancer PK/PD Core, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Dr, Tampa, Florida 33612, United States.
  • 4 Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States.
PMID: 41533987 DOI: 10.1021/acs.jmedchem.5c02086
Abstract

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, SR-4835 and its optimized analog SR-5037, 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.

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