2. Academic Validation
  3. Structure-Activity Relationship of USP5 Inhibitors

Structure-Activity Relationship of USP5 Inhibitors

  • J Med Chem. 2021 Oct 28;64(20):15017-15036. doi: 10.1021/acs.jmedchem.1c00889.
Mandeep K Mann 1 2,  Carlos A Zepeda-Velázquez 3,  Héctor González-Álvarez 2 3,  Aiping Dong 1,  Taira Kiyota 3,  Ahmed M Aman 3 4,  Peter Loppnau 1,  Yanjun Li 1,  Brian Wilson 3,  Cheryl H Arrowsmith 1 5 6,  Rima Al-Awar 2 3,  Rachel J Harding 1,  Matthieu Schapira 1 2
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, University of Toronto, 101 College Street, MaRS South Tower, 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 Ontario Institute for Cancer Research, 661 University Avenue, Toronto, Ontario M5G 0A3, Canada.
  • 4 Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada.
  • 5 Princess Margaret Cancer Centre, 661 University Avenue, Toronto, Ontario M5G 2C4, Canada.
  • 6 Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
PMID: 34648286 DOI: 10.1021/acs.jmedchem.1c00889
Abstract

USP5 is a Deubiquitinase that has been implicated in a range of diseases, including Cancer, but no USP5-targeting chemical probe has been reported to date. Here, we present the progression of a chemical series that occupies the C-terminal ubiquitin-binding site of a poorly characterized zinc-finger ubiquitin binding domain (ZnF-UBD) of USP5 and competitively inhibits the catalytic activity of the Enzyme. Exploration of the structure-activity relationship, complemented with crystallographic characterization of the ZnF-UBD bound to multiple ligands, led to the identification of 64, which binds to the USP5 ZnF-UBD with a KD of 2.8 μM and is selective over nine proteins containing structurally similar ZnF-UBD domains. 64 inhibits the USP5 catalytic cleavage of a di-ubiquitin substrate in an in vitro assay. This study provides a chemical and structural framework for the discovery of a chemical probe to delineate USP5 function in cells.

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