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Accelerating inhibitor discovery for deubiquitinating enzymes

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

Nature communications, 2023-02, Vol.14 (1), p.686-686, Article 686 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
Accelerating inhibitor discovery for deubiquitinating enzymes
Autor: 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
Assuntos: 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
É parte de: Nature communications, 2023-02, Vol.14 (1), p.686-686, Article 686
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descrição: 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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Accelerating inhibitor discovery for deubiquitinating enzymes

England: Nature Publishing Group

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