2. Academic Validation
  3. Re-Evaluating the Mechanism of Action of α,β-Unsaturated Carbonyl DUB Inhibitors b-AP15 and VLX1570: A Paradigmatic Example of Unspecific Protein Cross-linking with Michael Acceptor Motif-Containing Drugs

Re-Evaluating the Mechanism of Action of α,β-Unsaturated Carbonyl DUB Inhibitors b-AP15 and VLX1570: A Paradigmatic Example of Unspecific Protein Cross-linking with Michael Acceptor Motif-Containing Drugs

  • J Med Chem. 2020 Apr 9;63(7):3756-3762. doi: 10.1021/acs.jmedchem.0c00144.
Jennifer A Ward 1 2 3,  Adan Pinto-Fernandez 2 4,  Loïc Cornelissen 5,  Sarah Bonham 2,  Laura Díaz-Sáez 1 2,  Olivier Riant 5,  Kilian V M Huber 1 2,  Benedikt M Kessler 2,  Olivier Feron 4,  Edward W Tate 3
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, U.K.
  • 2 Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, U.K.
  • 3 Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, London W12 0BZ, U.K.
  • 4 Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, 57 Avenue Hippocrate B1.57.04, Brussels B-1200, Belgium.
  • 5 Institute of Condensed Matter and Nanosciences, MOST Division, Place Louis Pasteur, UCLouvain, Louvain-la-Neuve B-1348, Belgium.
PMID: 32109059 DOI: 10.1021/acs.jmedchem.0c00144
Abstract

Deubiquitinating Enzymes (DUBs) are a growing target class across multiple disease states, with several inhibitors now reported. b-AP15 and VLX1570 are two structurally related USP14/UCH-37 inhibitors. Through a proteomic approach, we demonstrate that these compounds target a diverse range of proteins, resulting in the formation of higher molecular weight (MW) complexes. Activity-based proteome profiling identified CIAPIN1 as a submicromolar covalent target of VLX1570, and further analysis demonstrated that high MW complex formation leads to aggregation of CIAPIN1 in intact cells. Our results suggest that in addition to DUB inhibition, these compounds induce nonspecific protein aggregation, providing molecular explanation for general cellular toxicity.

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