molecules of the month

The UC Berkeley and Novartis deubiquitinating enzyme-recruiting chimera (DUBTAC), NJH-2-057, has a warhead that covalently targets a non-catalytic allosteric cysteine on the deubiquitinase (DUB) OTUB1. The CFTR-binding moiety recruits OTUB1 to the mutant ion channel, ΔF508-CFTR, stabilizing the protein by preventing its polyubiquitination and degradation. This work provides an interesting proof of concept for targeted protein stabilization rather than degradation via DUB recruitment. We recently highlighted a number of new chimeric modalities, including ribonuclease recruiting chimeras (RIBOTACs), phosphatase recruiting chimeras (PhoRCs), LYTACs, and AUTACs, and this introduction of a deubiquitinating enzyme-recruiting chimera will add another valuable concept to the pharmacological toolbox. Note: This molecule was originally highlighted from an RXiV entry: https://doi.org/10.1101/2021.04.30.441959v1 - the link has been updated to reflect a new publication.