Deubiquitinase-targeting chimeras for targeted protein stabilization.

Autor:	Henning NJ; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Innovative Genomics Institute, Berkeley, CA, USA., Boike L; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Innovative Genomics Institute, Berkeley, CA, USA., Spradlin JN; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Innovative Genomics Institute, Berkeley, CA, USA., Ward CC; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Innovative Genomics Institute, Berkeley, CA, USA.; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA., Liu G; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Zhang E; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Innovative Genomics Institute, Berkeley, CA, USA., Belcher BP; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Innovative Genomics Institute, Berkeley, CA, USA., Brittain SM; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Hesse MJ; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Dovala D; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., McGregor LM; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Valdez Misiolek R; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Plasschaert LW; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Rowlands DJ; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Wang F; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Frank AO; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Emeryville, CA, USA., Fuller D; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Estes AR; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Innovative Genomics Institute, Berkeley, CA, USA., Randal KL; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Innovative Genomics Institute, Berkeley, CA, USA., Panidapu A; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Innovative Genomics Institute, Berkeley, CA, USA., McKenna JM; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Tallarico JA; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Schirle M; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Nomura DK; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA. dnomura@berkeley.edu.; Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA. dnomura@berkeley.edu.; Innovative Genomics Institute, Berkeley, CA, USA. dnomura@berkeley.edu.; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. dnomura@berkeley.edu.; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA. dnomura@berkeley.edu.
Jazyk:	angličtina
Zdroj:	Nature chemical biology [Nat Chem Biol] 2022 Apr; Vol. 18 (4), pp. 412-421. Date of Electronic Publication: 2022 Feb 24.
DOI:	10.1038/s41589-022-00971-2
Abstrakt:	Many diseases are driven by proteins that are aberrantly ubiquitinated and degraded. These diseases would be therapeutically benefited by targeted protein stabilization (TPS). Here we present deubiquitinase-targeting chimeras (DUBTACs), heterobifunctional small molecules consisting of a deubiquitinase recruiter linked to a protein-targeting ligand, to stabilize the levels of specific proteins degraded in a ubiquitin-dependent manner. Using chemoproteomic approaches, we discovered the covalent ligand EN523 that targets a non-catalytic allosteric cysteine C23 in the K48-ubiquitin-specific deubiquitinase OTUB1. We showed that a DUBTAC consisting of our EN523 OTUB1 recruiter linked to lumacaftor, a drug used to treat cystic fibrosis that binds ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR), robustly stabilized ΔF508-CFTR protein levels, leading to improved chloride channel conductance in human cystic fibrosis bronchial epithelial cells. We also demonstrated stabilization of the tumor suppressor kinase WEE1 in hepatoma cells. Our study showcases covalent chemoproteomic approaches to develop new induced proximity-based therapeutic modalities and introduces the DUBTAC platform for TPS. (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze:	MEDLINE
Externí odkaz:	Full text from SpringerLink