Abstract A053: Discovery and modular design of CDK12–DDB1 molecular glues for targeted Cyclin K degradation
Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) regulate transcriptional elongation, RNA processing, and DNA damage response programs essential for genome stability. Genetic alterations of CDK12 are recurrent across multiple tumor types, establishing this kinase as a compelling therapeutic target. While several ATP-competitive CDK12/13 inhibitors have been reported, recent evidence suggests that selected inhibitors can also function through induced-proximity mechanisms that promote selective protein degradation. SR-4835, originally discovered and reported by our group as a potent and selective ATP-competitive CDK12/13 inhibitor in 2019, has since become a widely used, commercially available tool compound to interrogate CDK12/13 biology in vitro and in vivo. Subsequent mechanistic studies revealed that SR-4835 acts as a molecular glue, promoting formation of a ternary complex between CDK12-cyclin K and the DDB1-CUL4-RBX1 E3 ubiquitin ligase, resulting in proteasome-mediated degradation of cyclin K. Notably, the extent of cyclin K degradation correlates with ternary complex formation rather than catalytic inhibition of CDK12. Building on this foundation, we applied structure-guided optimizations to demonstrate that molecular glue activity is not restricted to a single scaffold. Introduction of solvent-exposed benzimidazole substituents capable of engaging DDB1 enabled conversion of multiple CDK12-directed inhibitor scaffolds into effective cyclin K degraders, establishing structure-degradation relationships that are separable from classical kinase SAR. Proteome-wide profiling confirmed cyclin K as a consistently degraded target across optimized compounds. In vitro target engagement was confirmed using CRISPR/HiBiT-tagged reporter cell lines and quantitative immunofluorescence imaging, demonstrating compound-induced cyclin K degradation. In HER2+ and TNBC xenograft models, these compounds elicited rapid, dose-dependent cyclin K loss and robust antitumor efficacy, establishing tumor cyclin K degradation as a quantitative PD biomarker and demonstrating in vivo proof of mechanism in PDX cancer models. Advanced lead molecules across these series achieve a rare combination of high CDK12/13 selectivity, potent and durable cyclin K degradation, and favorable physicochemical, in vitro ADME, and in vivo PK properties, supporting progression toward IND-enabling preclinical safety evaluation. Thiyagamurthy Pandurangan, Anna Iermolaieva, Pompom Ghosh, John Mosior, Luxin Sun, Dylan Grassie, Matthias Geyer, Ernst Schönbrunn, William Roush, Derek Duckett, Andrii Monastyrskyi. Discovery and modular design of CDK12–DDB1 molecular glues for targeted Cyclin K degradation [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr A053.