Selective and Potent First‐in‐Class CRBN‐Dependent Molecular Glue Degraders of WW Domain‐Binding Protein 4

Abstract

ABSTRACT Targeted protein degradation via molecular glues represents a powerful modality for modulating “undruggable” proteins. Herein, through proteomic profiling of a CRBN‐binding library and rigorous structure‐activity relationship (SAR) refinement, we report the discovery of dWBP4‐1: a first‐in‐class, highly selective, CRBN‐dependent molecular glue degrader of the spliceosome‐associated scaffold protein WBP4. dWBP4‐1 induces rapid, nanomolar degradation of WBP4 via a canonical G‐loop‐mediated mechanism, exhibiting exceptional proteome‐wide selectivity with negligible transcriptomic or alternative splicing perturbation. Leveraging this highly specific target‐glue interaction, we mapped the minimal WBP4 degron to a 41‐amino‐acid sequence to establish a compact, inducible chemical‐genetic platform termed wTAG. When fused to diverse proteins of interest, wTAG enables robust, monotonic degradation devoid of the hook effect. While the wTAG system is highly versatile, we delineate its boundaries when applied to challenging targets like Cyclin D1, where factors such as steric hindrance, lysine availability, complex sequestration, and tag accessibility (N‐ vs. C‐terminal fusion) must be carefully interrogated. Collectively, this study highlights the discovery of a highly selective WBP4 molecular glue and translates its underlying degron into a robust tool for precise protein control.