2. Academic Validation
  3. A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation

A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation

  • Nat Commun. 2025 Nov 19;16(1):10157. doi: 10.1038/s41467-025-65094-3.
Gerasimos Langousis 1,  Pablo Gainza 1,  Moritz Hunkeler 2,  Despoina Kapsitidou 1,  Etienne J Donckele 1,  Stefano Annunziato 1,  Lars Wiedmer 1,  Katherine F M Jones 1,  Bradley DeMarco 1,  Chao Quan 1,  Richard D Bunker 1,  Kevin J Lumb 1,  Bernhard Fasching 1,  John C Castle 1,  Sharon A Townson 1,  Débora Bonenfant 3
Affiliations

Affiliations

  • 1 Monte Rosa Therapeutics AG, Basel, Switzerland.
  • 2 University of Basel, BioEM Lab, Basel, Switzerland.
  • 3 Monte Rosa Therapeutics AG, Basel, Switzerland. [email protected].
PMID: 41258141 DOI: 10.1038/s41467-025-65094-3
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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