A molecular glue degrader-antibody conjugate for HER2-targeted cyclin K degradation

Antibody-conjugated CCNK molecular glue degrader Tz-SS2009 drives ubiquitin-proteasome–dependent CCNK degradation and stronger antiproliferative effects in HER2-positive breast cancer cells than HER2-negative cells.

• Why it matters: CDK12/CCNK is frequently co-amplified with HER2, but the complex’s broad expression and essential roles may narrow the therapeutic window for potent molecular glue degraders.
• What they did: SAS1001, a CCNK molecular glue with a solvent-exposed piperazine for linker attachment, was conjugated to trastuzumab to form Tz-SS2009, then tested for HER2-dependent internalization, CCNK degradation, and downstream proteome changes.
• The result: Whole proteome analysis showed CCNK depletion and transcriptional-regulation–consistent downstream effects, supporting antibody-mediated redistribution of a molecular glue degrader toward antigen-positive cells.

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