Accelerating inhibitor discovery for deubiquitinating enzymes

Wai Cheung Chan, Xiaoxi Liu, Robert S. Magin, Nicholas M. Girardi, Scott B. Ficarro, Wanyi Hu, Maria I. Tarazona Guzman, Cara A. Starnbach, Alejandra Felix, Guillaume Adelmant, Anthony C. Varca, Bin Hu, Ariana S. Bratt, Ethan DaSilva, Nathan J. Schauer, Isabella Jaen Maisonet, Emma K. Dolen, Anthony X. Ayala, Jarrod A. Marto () and Sara J. Buhrlage ()
Additional contact information
Wai Cheung Chan: Dana-Farber Cancer Institute
Xiaoxi Liu: Dana-Farber Cancer Institute
Robert S. Magin: Dana-Farber Cancer Institute
Nicholas M. Girardi: Dana-Farber Cancer Institute
Scott B. Ficarro: Dana-Farber Cancer Institute
Wanyi Hu: Dana-Farber Cancer Institute
Maria I. Tarazona Guzman: Dana-Farber Cancer Institute
Cara A. Starnbach: Dana-Farber Cancer Institute
Alejandra Felix: Dana-Farber Cancer Institute
Guillaume Adelmant: Dana-Farber Cancer Institute
Anthony C. Varca: Dana-Farber Cancer Institute
Bin Hu: Dana-Farber Cancer Institute
Ariana S. Bratt: Dana-Farber Cancer Institute
Ethan DaSilva: Dana-Farber Cancer Institute
Nathan J. Schauer: Dana-Farber Cancer Institute
Isabella Jaen Maisonet: Dana-Farber Cancer Institute
Emma K. Dolen: Dana-Farber Cancer Institute
Anthony X. Ayala: Dana-Farber Cancer Institute
Jarrod A. Marto: Dana-Farber Cancer Institute
Sara J. Buhrlage: Dana-Farber Cancer Institute

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-36246-0

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