Accelerating inhibitor discovery for deubiquitinating enzymes

Deubiquitinating enzymes (DUBs) are an emerging drug target class of ~100 proteases that cleave ubiquitin from protein substrates to regulate many cellular processes. A lack of selective chemical probes impedes pharmacologic interrogation of this important gene family. DUBs engage their cognate liga...

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Bibliographic Details
Published in:	Nature communications 2023-02, Vol.14 (1), p.686-686, Article 686
Main Authors:	Chan, Wai Cheung, Liu, Xiaoxi, Magin, Robert S, Girardi, Nicholas M, Ficarro, Scott B, Hu, Wanyi, Tarazona Guzman, Maria I, Starnbach, Cara A, Felix, Alejandra, Adelmant, Guillaume, Varca, Anthony C, Hu, Bin, Bratt, Ariana S, DaSilva, Ethan, Schauer, Nathan J, Jaen Maisonet, Isabella, Dolen, Emma K, Ayala, Anthony X, Marto, Jarrod A, Buhrlage, Sara J
Format:	Article
Language:	eng
Subjects:	Deubiquitinating Enzymes - metabolism Endopeptidases - metabolism Enzyme inhibitors Enzymes Interrogation Libraries Mass spectrometry Mass spectroscopy Optimization Peptide Hydrolases - metabolism Proteins Selectivity Structure-Activity Relationship Structure-activity relationships Substrates Therapeutic targets Ubiquitin Ubiquitin - metabolism Ubiquitination
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Summary:	Deubiquitinating enzymes (DUBs) are an emerging drug target class of ~100 proteases that cleave ubiquitin from protein substrates to regulate many cellular processes. A lack of selective chemical probes impedes pharmacologic interrogation of this important gene family. DUBs engage their cognate ligands through a myriad of interactions. We embrace this structural complexity to tailor a chemical diversification strategy for a DUB-focused covalent library. Pairing our library with activity-based protein profiling as a high-density primary screen, we identify selective hits against 23 endogenous DUBs spanning four subfamilies. Optimization of an azetidine hit yields a probe for the understudied DUB VCPIP1 with nanomolar potency and in-family selectivity. Our success in identifying good chemical starting points as well as structure-activity relationships across the gene family from a modest but purpose-build library challenges current paradigms that emphasize ultrahigh throughput in vitro or virtual screens against an ever-increasing scope of chemical space.
ISSN:	2041-1723 2041-1723