Mapping the latent CRBN-molecular glue degrader interactome

ABSTRACT

Molecular glue degraders (MGDs) are a transformative modality in drug discovery. MGDs that work in concert with the E3 ligase CRL4CRBN 22 can degrade a range of substrates through tailored MGDs. To explore CRL4CRBN 23 reprogrammability, we tested 24 whether reported CRBN-MGD substrates are part of a network of latent CRBN 25 interactors, detectable with generic CRBN-MGDs. Leveraging highly parallel interaction measurement (GluePCA) between CRL4CRBN 26 and human zinc-fingers 27 (ZFs), we identified ~210 ZFs bound to CRBN-pomalidomide, where top binders are 28 already reported as degraded by dedicated MGDs. To map latent CRBN-MGDs 29 interactions proteome-wide, and thus define the immediately accessible CRBN target 30 space, we combined AI-derived protein surface queries (MaSIF-mimicry) with 31 GluePCA. This pipeline identified 6 known and 43 novel CRBN-pomalidomide binders, 32 thereby providing privileged starting points for MGD development. We expect this 33 binding-focused, highly parallel workflow to be readily applicable to other MGD/E3 34 ligase systems, extending the target landscape of this emerging drug class.