Targeting CDK12 condensates at nuclear speckles with rationally designed cyclin K molecular glue degraders

Abstract

Transcriptional machinery often operates in the configuration of biomolecular condensates, presenting emerging opportunities to develop therapies targeting transcriptionally addicted malignancies. In this study, we discovered that cyclin-dependent kinase 12 (CDK12), a key regulator of transcription elongation, formed dynamic liquid-like droplets at nuclear speckles, a process enhanced by high CDK12 expression and CDK12 inhibitor exposure. Notably, CDK12 condensation limited sensitivity to kinase inhibition, potentially through enhanced cyclin K recruitment and local enrichment of CDK12-cyclin K complexes. To disrupt these assemblies, we rationally designed HQY1428, a potent modular cyclin K molecular glue degrader that coupled CDK12-binding and DDB1-engaging moieties. Structural and biochemical analyses showed that HQY1428 promoted CDK12-DDB1 association and rapid cyclin K degradation, accompanied by CDK12 depletion and loss of CDK12 condensates. Functionally, HQY1428 treatment perturbed oncogenic transcription and suppressed ovarian cancer growth in vitro and in vivo. Given the frequent genomic co-amplification of CDK12 and ERBB2 across diverse human cancers, we showed that combining HQY1428 with HER2 inhibitors provided synergistic therapeutic benefits. Collectively, our findings establish CDK12 condensation at nuclear speckles as an exploitable vulnerability and support targeting CDK12 condensates with cyclin K molecular glue degraders.