Accelerating inhibitor discovery for deubiquitinating enzymes.

Autor:	Chan WC; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Liu X; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Magin RS; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Girardi NM; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Ficarro SB; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA, USA.; Center for Emergent Drug Targets, Dana-Farber Cancer Institute, Boston, MA, USA., Hu W; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Tarazona Guzman MI; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Starnbach CA; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Felix A; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Adelmant G; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA, USA., Varca AC; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Hu B; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Bratt AS; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., DaSilva E; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Schauer NJ; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Jaen Maisonet I; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Dolen EK; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Ayala AX; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Marto JA; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA. jarrod_marto@dfci.harvard.edu.; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA, USA. jarrod_marto@dfci.harvard.edu.; Center for Emergent Drug Targets, Dana-Farber Cancer Institute, Boston, MA, USA. jarrod_marto@dfci.harvard.edu.; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. jarrod_marto@dfci.harvard.edu., Buhrlage SJ; Department of Cancer Biology and the Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA. saraj_buhrlage@dfci.harvard.edu.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. saraj_buhrlage@dfci.harvard.edu.; Center for Emergent Drug Targets, Dana-Farber Cancer Institute, Boston, MA, USA. saraj_buhrlage@dfci.harvard.edu.; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. saraj_buhrlage@dfci.harvard.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2023 Feb 08; Vol. 14 (1), pp. 686. Date of Electronic Publication: 2023 Feb 08.
DOI:	10.1038/s41467-023-36246-0
Abstrakt:	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. (© 2023. The Author(s).)
Databáze:	MEDLINE
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