Mining the CRBN target space redefines rules for molecular glue–induced neosubstrate recognition
Georg Petzold, Pablo Gaínza, Stefano Annunziato, Ilaria Lamberto, Peter Trenh, Laura A. McAllister, Bradley DeMarco, Laura Schwander, R.D. Bunker, Mary Zlotosch, Rohitha Sriramaratnam, Samuel Gilberto, Gerasimos Langousis, Etienne J. Donckèle, Cynthia Quan, Vaïk Strande, Gian Marco De Donatis, Shanique Alabi, Jessica Alers, Michelle Matysik, Camille Staehly, Aurélie Dubois, Arnaud Osmont, Mackenzie Garskovas, David Lyon, L. Wiedmer, Vladimiras Oleinikovas, Raphael Lieberherr, Nooreen Rubin, Daniel T. Lam, Xavier Lucas, Elisa Liardo, Nina Ilic Widlund, Andreas Ritzén, Ramon Miguel Caceres, Dominico Vigil, Jennifer Tsai, Owen B. Wallace, Marisa Peluso, Amine Sadok, Ralph Tiedt, Alison M. Paterson, Vladislav Zarayskiy, Bernhard Fasching, Débora Bonenfant, Markus Warmuth, John C. Castle, Sharon A. Townson
Abstract
The CRL4 CRBN 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 β-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 CRL4 CRBN through next-generation molecular glue degraders.