ProxiCapture reveals context-dependent CRBN interactome landscape of molecular glue degraders

Molecular glue degraders represent a rapidly expanding class of small molecules that reprogram E3 ubiquitin ligases to ubiquitinate and degrade disease-relevant proteins. Despite their therapeutic potential, the rational design of molecular glues remains challenging, underscoring the need for unbiased discovery strategies to identify new chemical targets. To address this challenge, we developed ProxiCapture, an affinity-based proteomics workflow that models the systemic behavior of molecular glues (MGs) by combining purified CRBN-ΔHBD protein with native cell or tissue lysates. ProxiCapture enables proteome-wide identification of degrader-dependent CRBN-protein interaction across diverse biological contexts.