Discovery of Small Molecule Antagonists of the USP5 Zinc Finger Ubiquitin-Binding Domain

  • J Med Chem. 2019 Nov 27;62(22):10144-10155. doi: 10.1021/acs.jmedchem.9b00988.
Mandeep K Mann  1  2 ,  Ivan Franzoni  3 ,  Renato Ferreira de Freitas  1 ,  Wolfram Tempel  1 ,  Scott Houliston  4 ,  Leanna Smith  1 ,  Masoud Vedadi  1  2 ,  Cheryl H Arrowsmith  1  4 ,  Rachel J Harding  1 ,  Matthieu Schapira  1  2
Affiliations
  • 1. Structural Genomics Consortium, University of Toronto, MaRS Centre , South Tower, 101 College St., Suite 700 , Toronto , Ontario M5G 1L7 , Canada.
  • 2. Department of Pharmacology and Toxicology , University of Toronto , 1 King's College Circle , Toronto , Ontario M5S 1A8 , Canada.
  • 3. Department of Chemistry , University of Toronto , 80 St. George St. , Toronto , Ontario M5S 3H6 , Canada.
  • 4. University Health Network , 661 University Avenue , Toronto , Ontario M5G 2C4 , Canada.
PMID: 31663737 DOI: 10.1021/acs.jmedchem.9b00988
Abstract

USP5 disassembles unanchored polyubiquitin chains to recycle free monoubiquitin, and is one of the 12 ubiquitin specific proteases featuring a zinc finger ubiquitin-binding domain (ZnF-UBD). This distinct structural module has been associated with substrate positioning or allosteric modulation of catalytic activity, but its cellular function remains unclear. We screened a chemical library focused on the ZnF-UBD of USP5, crystallized hits in complex with the protein, and generated a preliminary structure-activity relationship, which enables the development of more potent and selective compounds. This work serves as a framework for the discovery of a chemical probe to delineate the function of USP5 ZnF-UBD in proteasomal degradation and Other ubiquitin signaling pathways in health and disease.

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