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

Cyclin-dependent kinase 12 (CDK12) is an attractive therapeutic target due to its critical role in transcriptional regulation and DNA damage response and is frequently co-amplified with ERBB2 (HER2) in breast cancer. CDK12 forms an active complex with its obligate partner cyclin K (CCNK), and pharmacological degradation of CCNK has emerged as a promising strategy for disrupting CDK12-dependent transcriptional programs. However, the broad expression and essential functions of the CDK12/CCNK complex may limit the therapeutic window of highly potent molecular glue degraders. Here, we investigate whether antibody-mediated delivery can impart cellular selectivity to a molecular glue degrader through targeting the HER2 receptor. Molecular glues lack the modular architecture of PROTACs, thus linker placement can be the central design problem. We designed SAS1001, a CCNK molecular glue degrader with a solvent-exposed piperazine primed for linker attachment. SAS1001 induced potent and ubiquitin-proteasome system-dependent degradation of CCNK and inhibited proliferation in a range of breast cancer cells. Conjugation to trastuzumab (Tz) generated the HER2-targeted degrader-antibody conjugate Tz-SS2009, which internalized preferentially in HER2-positive cells and produced enhanced CCNK degradation and antiproliferative effects, relative both to HER2-negative cells and to an isotype-matched non-targeting conjugate. Whole proteome analysis further demonstrated CCNK depletion and revealed downstream changes consistent with established roles of the CDK12/CCNK complex in transcriptional regulation. These findings demonstrate that antibody-mediated delivery can redistribute the cellular activity of a potent molecular glue degrader towards antigen-positive cells. In the CR8/DS18 purine series, substitution at a solvent-exposed position preserved CCNK degradation when the degrader was delivered on a full-length IgG. More broadly, this work extends antibody-directed degradation beyond the CRBN-based glues that have dominated the field and illustrates how structural characterization of a glue scaffold can identify a linker attachment point that does not compromise activity.