Mining the CRBN target space redefines rules for molecular glue-induced neosubstrate recognition

• 成果类型: Article
• 署名作者: Petzold, Georg; Gainza, Pablo; Annunziato, Stefano; Lamberto, Ilaria; Trenh, Peter; McAllister, Laura A.; DeMarco, Bradley; Schwander, Laura; Bunker, Richard D.; Zlotosch, Mary; Sriramaratnam, Rohitha; Gilberto, Samuel; Langousis, Gerasimos; Donckele, Etienne J.; Quan, Chao; Strande, Vaik; De Donatis, Gian Marco; Alabi, Shanique B.; Alers, Jessica; Matysik, Michelle; Staehly, Camille; Dubois, Aurelie; Osmont, Arnaud; Garskovas, Mackenzie; Lyon, David; Wiedmer, Lars; Oleinikovas, Vladimiras; Lieberherr, Raphael; Rubin, Nooreen T.; Lam, Daniel T.; Lucas, Xavier; Liardo, Elisa; Widlund, Nina Ilic; Ritzen, Andreas; Caceres, Ramon Miguel; Vigil, Dominico; Tsai, Jennifer; Wallace, Owen; Peluso, Marisa; Sadok, Amine; Tiedt, Ralph; Paterson, Alison M.; Zarayskiy, Vladislav; Fasching, Bernhard; Bonenfant, Debora; Warmuth, Markus; Castle, John C.; Townson, Sharon A.
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11124
• DOI: 10.1126/science.adt6736
• 发表日期: 2025-07-03
• 关键词: lenalidomide; degradation; downstream; degrader; ikaros

摘要

The CRL4CRBN E3 ubiquitin ligase is the target of molecular glue degrader compounds that reprogram ligase specificity to induce the degradation of clinically relevant neosubstrate proteins. Known cereblon (CRBN) neosubstrates share a generalizable beta-hairpin G-loop recognition motif that allows for the systematic exploration of the CRBN target space. Computational mining approaches using structure- and surface-based matchmaking algorithms predict more than 1600 CRBN-compatible G-loop proteins across the human proteome, including the newly discovered helical G-loop motif, and identify the noncanonical neosubstrate binding mode of VAV1 that engages CRBN through a molecular surface mimicry mechanism. This work broadens the CRBN target space, redefines rules for neosubstrate recognition, and establishes a platform for the elimination of challenging drug targets by repurposing CRL4CRBN through next-generation molecular glue degraders.