1. Identification of small-molecule inhibitors of USP2a
- Author
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Bartosz J. Zieba, Grzegorz Dubin, Michael Sattler, Marcin Tomala, Lukasz Skalniak, Katarzyna Magiera-Mularz, Sylwia Krzanik, Tad A. Holak, Bogdan Musielak, Marcin Pustula, Grzegorz M. Popowicz, and Katarzyna Kubica
- Subjects
0301 basic medicine ,Deubiquitinating enzyme ,Small Molecule Libraries ,03 medical and health sciences ,Structure-Activity Relationship ,0302 clinical medicine ,Cyclin D1 ,Ubiquitin ,Drug Discovery ,Endopeptidases ,Humans ,Enzyme Inhibitors ,Pharmacology ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Activator (genetics) ,Organic Chemistry ,Deubiquitinase ,Small-molecular Inhibitors ,Heterocyclics ,Anticancer ,General Medicine ,Small molecule ,Protein ubiquitination ,Cell biology ,030104 developmental biology ,Proteasome ,030220 oncology & carcinogenesis ,biology.protein ,Pharmacophore ,Ubiquitin Thiolesterase - Abstract
USP2a is a deubiquitinating protease that rescues its target proteins from destruction by the proteasome by reversing the process of protein ubiquitination. USP2a shows oncogenic properties in vivo and has been found to be a specific activator of cyclin D1. Many types of cancers are addicted to cyclin D1 expression. Targeting USP2a is a promising strategy for cancer therapy but little progress has been made in the field of inhibition of USP2a. Using NMR-based fragment screening and biophysical binding assays, we have discovered small molecules that bind to USP2a. Iterations of fragment combination and structure-driven design identified two 5-(2-thienyl)-3-isoxazoles as the inhibitors of the USP2a-ubiquitin protein-protein interaction. The affinity of these molecules for the catalytic domain of USP2a parallels their ability to interfere with USP2a binding to ubiquitin in vitro. Altogether, our results establish the 5-(2-thienyl)-3-isoxazole pharmacophore as an attractive starting point for lead optimization.
- Published
- 2018