Development of a covalent cereblon-based PROTAC employing a fluorosulfate warhead
Radosław P. Nowak, Leah Ragosta, Fidel Huerta, Hu Liu, Scott B. Ficarro, Justin T. Cruite, Rebecca J. Metivier, Katherine A. Donovan, Jarrod A. Marto, Eric S. Fischer, Breanna L. Zerfas, Lyn H. Jones
Abstract
, and in cells the BRD4 degrader is insensitive to wash-out and competition by potent reversible CRBN ligands, reflecting enhanced pharmacodynamics. We anticipate that covalent CRBN-based PROTACs will enhance degradation efficiencies, thus expanding the scope of addressable targets using the heterobifunctional degrader modality.
Topics & Concepts
WarheadCereblonCovalent bondChemistryEngineeringBiochemistryOrganic chemistryAerospace engineeringUbiquitin ligaseGeneUbiquitinProtein Degradation and InhibitorsPeptidase Inhibition and AnalysisUbiquitin and proteasome pathways