2. Academic Validation
  3. Small Molecule Inhibition of the Ubiquitin-specific Protease USP2 Accelerates cyclin D1 Degradation and Leads to Cell Cycle Arrest in Colorectal Cancer and Mantle Cell Lymphoma Models

Small Molecule Inhibition of the Ubiquitin-specific Protease USP2 Accelerates cyclin D1 Degradation and Leads to Cell Cycle Arrest in Colorectal Cancer and Mantle Cell Lymphoma Models

  • J Biol Chem. 2016 Nov 18;291(47):24628-24640. doi: 10.1074/jbc.M116.738567.
Mindy I Davis 1,  Rajan Pragani 1,  Jennifer T Fox 1,  Min Shen 1,  Kalindi Parmar 2,  Emily F Gaudiano 2,  Li Liu 1,  Cordelle Tanega 1,  Lauren McGee 1,  Matthew D Hall 1,  Crystal McKnight 1,  Paul Shinn 1,  Henrike Nelson 1,  Debasish Chattopadhyay 3,  Alan D D'Andrea 2,  Douglas S Auld 1,  Larry J DeLucas 3,  Zhuyin Li 1,  Matthew B Boxer 4,  Anton Simeonov 5
Affiliations

Affiliations

  • 1 From the NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20892.
  • 2 the Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, and.
  • 3 the Center for Structural Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
  • 4 From the NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20892,. Electronic address: boxerm@mail.nih.gov.
  • 5 From the NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20892,. Electronic address: asimeono@mail.nih.gov.
PMID: 27681596 DOI: 10.1074/jbc.M116.738567
Abstract

Deubiquitinases are important components of the protein degradation regulatory network. We report the discovery of ML364, a small molecule inhibitor of the Deubiquitinase USP2 and its use to interrogate the biology of USP2 and its putative substrate cyclin D1. ML364 has an IC50 of 1.1 μm in a biochemical assay using an internally quenched fluorescent di-ubiquitin substrate. Direct binding of ML364 to USP2 was demonstrated using microscale thermophoresis. ML364 induced an increase in cellular cyclin D1 degradation and caused cell cycle arrest as shown in Western blottings and flow cytometry assays utilizing both Mino and HCT116 Cancer cell lines. ML364, and not the inactive analog 2, was antiproliferative in Cancer cell lines. Consistent with the role of cyclin D1 in DNA damage response, ML364 also caused a decrease in homologous recombination-mediated DNA repair. These effects by a small molecule inhibitor support a key role for USP2 as a regulator of cell cycle, DNA repair, and tumor cell growth.

Keywords

USP2; cancer biology; cell cycle; cyclin D1; drug discovery; enzyme inhibitor; ubiquitin-dependent protease; ubiquitylation (ubiquitination).

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