Molecular Glues Recruiting RNF213 As an E3 Ligase for Targeted Protein Degradation: A Minimal Dibromoacetamide...

Targeted protein degradation (TPD) is a promising therapeutic strategy, yet its application remains constrained by the limited repertoire of available E3 ubiquitin ligases, primarily CRBN and VHL. Here, we identify RNF213 as a recruitable E3 ligase that mediates protein degradation induced by molecular glue degraders. We developed CYB-5067 by equipping the pan-FGFR inhibitor Infigratinib with a minimal dibromoacetamide covalent warhead. This covalent molecular glue recruits RNF213 to potently degrade FGFR1-4, with the strongest effect on FGFR2 (DC₅₀ = 27 nM, D_max = 96%). CYB-5067 outperforms parent inhibitors in vitro (IC₅₀ = 3.8 nM) and shows comparable antitumor efficacy in vivo (TGI = 94.6%), with sustained target suppression and no apparent hook effects under the tested conditions. Notably, the dibromoacetamide warhead is transplantable, enabling selective degradation of other challenging targets such as WEE1 and CDK12, which regulate cell-cycle progression and transcription. This offers a rational strategy for creating molecular glues. Our work identifies RNF213 as an exploitable ligase for TPD and establishes covalent molecular glues as a modular platform. This strategy expands the scope of degrader design beyond conventional E3 ligases, offering an avenue for developing potent and selective therapeutics.