| Literature DB >> 35210618 |
Nathaniel J Henning1,2,3, Lydia Boike1,2,3, Jessica N Spradlin1,2,3, Carl C Ward2,3,4, Gang Liu2,5, Erika Zhang1,2,3, Bridget P Belcher1,2,3, Scott M Brittain2,5, Matthew J Hesse2,6, Dustin Dovala2,6, Lynn M McGregor2,5, Rachel Valdez Misiolek5, Lindsey W Plasschaert5, David J Rowlands5, Feng Wang2,6, Andreas O Frank2,6, Daniel Fuller2,5, Abigail R Estes1,2,3, Katelyn L Randal1,2,3, Anoohya Panidapu1,2,3, Jeffrey M McKenna2,5, John A Tallarico2,5, Markus Schirle2,5, Daniel K Nomura7,8,9,10,11.
Abstract
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.Entities:
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Year: 2022 PMID： 35210618 DOI： 10.1038/s41589-022-00971-2
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 16.174