Trastuzumab-linked molecular glue steers cyclin K degradation toward HER2-positive breast cancer cells
- The cyclin K glue degrader SAS1001 uses a solvent-exposed piperazine as its linker handle, tackling the lack of an obvious attachment site on glue scaffolds.
- It degraded cyclin K via the ubiquitin-proteasome system and slowed growth across breast cancer cell lines.
- Conjugated to trastuzumab, it entered HER2-positive cells preferentially, beating HER2-negative cells and a non-targeting conjugate; proteomics confirmed cyclin K loss.
💡 Points Based on the abstract
A solvent-exposed piperazine is a sensible exit vector, but glues are fickle: small changes near the DDB1-facing surface can abolish the ternary complex. Degradation needs showing for the linker-bearing payload, with cleavable against non-cleavable linkers, plus a CDK12 kinase-inhibitor control to separate degradation from plain CDK12 inhibition. And does the released glue reach enough intracellular exposure?
📄 Paper · bioRxiv ↗ A molecular glue degrader-antibody conjugate for HER2-targeted cyclin K degradation