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

HQY1428, a cyclin K molecular glue degrader, promotes CDK12–DDB1 association and rapid cyclin K degradation, depleting CDK12 condensates at nuclear speckles.

• Why it matters: CDK12 forms liquid-like droplets at nuclear speckles, and this condensation can limit sensitivity to kinase inhibition, leaving a therapeutic vulnerability to exploit.
• What they did: The study used structural and biochemical analyses to show HQY1428 drives CDK12–DDB1 binding and cyclin K degradation, then tested effects on oncogenic transcription and ovarian cancer growth in vitro and in vivo.
• The result: HQY1428 perturbed oncogenic transcription and suppressed ovarian cancer growth, and in cancers with CDK12 and ERBB2 co-amplification it synergized with HER2 inhibitors.

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