2. Academic Validation
  3. Molecular glues that inhibit specific Zn2+-dependent DUB activity and inflammation

Molecular glues that inhibit specific Zn2+-dependent DUB activity and inflammation

  • bioRxiv. 2024 Sep 7:2024.09.07.611787. doi: 10.1101/2024.09.07.611787.
Francesca Chandler 1,  Poli Adi Narayana Reddy 2,  Smita Bhutda 3,  Rebecca L Ross 4 5,  Miriam Walden 1,  Kieran Walker 4,  Stefano Di Donato 4 5,  Joel A Cassel 2,  Michael A Prakesch 6,  Ahmed Aman 6,  Alessandro Datti 7,  Lisa J Campbell 1,  Martina Foglizzo 1,  Lillie Bell 1,  Daniel N Stein 3,  James R Ault 1,  Rima S Al-Awar 6 8,  Antonio N Calabrese 1,  Frank Sicheri 9 10 11,  Francesco Del Galdo 4 5,  Joseph M Salvino 2,  Roger A Greenberg 3,  Elton Zeqiraj 1
Affiliations

Affiliations

  • 1 Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK.
  • 2 The Wistar Cancer Center for Molecular Screening, The Wistar Institute, Philadelphia, PA, USA.
  • 3 Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 4 Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UK.
  • 5 NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals, NHS Trust, Chapel Allerton Hospital, Leeds, UK.
  • 6 Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
  • 7 Department of Agriculture, Food, and Environmental Sciences, University of Perugia, Perugia, Italy.
  • 8 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
  • 9 Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
  • 10 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 11 Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
PMID: 39282282 DOI: 10.1101/2024.09.07.611787
Abstract

Deubiquitylases (DUBs) play a pivotal role in cell signalling and are often regulated by homo- or hetero-interactions within protein complexes. The BRCC36 isopeptidase complex (BRISC) regulates inflammatory signalling by selectively cleaving K63-linked polyubiquitin chains on Type I interferon receptors (IFNAR1). BRCC36 is a Zn2+-dependent JAMM/MPN DUB, a challenging ubiquitin Protease class for the design of selective inhibitors. We identified first-in-class DUB inhibitors that act as BRISC Molecular Glues (BLUEs). BLUEs inhibit DUB activity by stabilising a BRISC dimer consisting of 16 subunits. The BLUE-stabilised BRISC dimer is an autoinhibited conformation, whereby the active sites and interactions with the recruiting subunit SHMT2 are blocked. This unique mode of action leads to highly selective inhibitors for BRISC over related complexes with the same catalytic subunit, splice variants and other JAMM/MPN DUBs. Structure-guided inhibitor resistant mutants confirm BLUEs on-target activity in cells, and BLUE treatment results in reduced interferon-stimulated gene (ISG) expression in human peripheral blood mononuclear cells from Scleroderma patients, a disease linked with aberrant IFNAR1 activation. BLUEs represent a new class of molecules with potential utility in Type I interferon-mediated diseases and a template for designing selective inhibitors of large protein complexes by promoting protein-protein interactions instead of blocking them.

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