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Updated: Jan 11, 2026

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation
Gerasimos Langousis1, Pablo Gainza1, Moritz Hunkeler2
1Monte Rosa Therapeutics AG, Basel, Switzerland.
Abstract:
Cereblon (CRBN) is an E3 ubiquitin ligase widely harnessed for targeted protein degradation (TPD). We report the discovery of a molecular glue degrader (MGD), MRT-31619, that drives homo-dimerization of CRBN and promotes its fast, potent, and selective degradation by the ubiquitin proteasome system. Interestingly, the cryo-electron microscopy (cryo-EM) structure of the CRBN homodimer reveals a unique mechanism whereby two molecular glues assemble into a helix-like structure and drive ternary complex formation by mimicking a neosubstrate G-loop degron. This CRBN chemical knockout offers a valuable tool to elucidate the molecular mechanism of MGDs, to investigate its endogenous substrates and understand their physiological roles.
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