2. Academic Validation
  3. Deubiquitinase-targeting chimeras for targeted protein stabilization

Deubiquitinase-targeting chimeras for targeted protein stabilization

  • Nat Chem Biol. 2022 Apr;18(4):412-421. doi: 10.1038/s41589-022-00971-2.
Nathaniel J Henning  # 1 2 3,  Lydia Boike  # 1 2 3,  Jessica N Spradlin 1 2 3,  Carl C Ward 2 3 4,  Gang Liu 2 5,  Erika Zhang 1 2 3,  Bridget P Belcher 1 2 3,  Scott M Brittain 2 5,  Matthew J Hesse 2 6,  Dustin Dovala 2 6,  Lynn M McGregor 2 5,  Rachel Valdez Misiolek 5,  Lindsey W Plasschaert 5,  David J Rowlands 5,  Feng Wang 2 6,  Andreas O Frank 2 6,  Daniel Fuller 2 5,  Abigail R Estes 1 2 3,  Katelyn L Randal 1 2 3,  Anoohya Panidapu 1 2 3,  Jeffrey M McKenna 2 5,  John A Tallarico 2 5,  Markus Schirle 2 5,  Daniel K Nomura 7 8 9 10 11
Affiliations

Affiliations

  • 1 Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
  • 2 Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.
  • 3 Innovative Genomics Institute, Berkeley, CA, USA.
  • 4 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
  • 5 Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
  • 6 Novartis Institutes for BioMedical Research, Emeryville, CA, USA.
  • 7 Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA. [email protected].
  • 8 Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA. [email protected].
  • 9 Innovative Genomics Institute, Berkeley, CA, USA. [email protected].
  • 10 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. [email protected].
  • 11 Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA. [email protected].
  • # Contributed equally.
PMID: 35210618 DOI: 10.1038/s41589-022-00971-2
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.

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