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.

分子胶降解剂（Molecular glue degraders）是一类快速发展的小分子化合物，可重编程E3泛素连接酶，使其泛素化并降解疾病相关蛋白。尽管其具备治疗潜力，但分子胶的理性设计仍颇具挑战，这凸显了开发无偏发现策略以识别新型化学靶点的迫切需求。为应对这一挑战，我们开发了ProxiCapture——一种基于亲和蛋白质组学的工作流程，该流程通过将纯化的CRBN-ΔHBD蛋白与天然细胞或组织裂解物相结合，模拟分子胶的系统行为。ProxiCapture可在多种生物学背景下，实现全蛋白质组范围内降解剂依赖型CRBN-蛋白相互作用的鉴定。