Discovery of novel selenium derivatives as Pin1 inhibitors by high-throughput screening.

Amit Subedi, Takeshi Shimizu, Akihide Ryo, Emiko Sanada, Nobumoto Watanabe, Hiroyuki Osada

Journal: Biochemical and biophysical research communications 2017;474(3):528-533

PMID: 27120460

Full Text on Elsevier Science View on PubMed

Abstract

Peptidyl prolyl cis/trans isomerization by Pin1 regulates various oncogenic signals during cancer progression, and its inhibition through multiple approaches has established Pin1 as a therapeutic target. However, lack of simplified screening systems has limited the discovery of potent Pin1 inhibitors. We utilized phosphorylation-dependent binding of Pin1 to its specific substrate to develop a screening system for Pin1 inhibitors. Using this system, we screened a chemical library, and identified a novel selenium derivative as Pin1 inhibitor. Based on structure-activity guided chemical synthesis, we developed more potent Pin1 inhibitors that inhibited cancer cell proliferation.

Address: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan; Graduate School of Science and Engineering, Saitama University, Saitama, 338-8570, Japan.; Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan.; Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Kanagawa, 236-0004, Japan.; Bio-Active Compounds Discovery Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan.; Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan; Bio-Active Compounds Discovery Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan.; Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan; Graduate School of Science and Engineering, Saitama University, Saitama, 338-8570, Japan. Electronic address: [email protected].

DOI: 10.1016/j.bbrc.2016.04.124

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MeSH Terms: Binding Sites, Cell Line, Tumor, Drug Evaluation, Preclinical, High-Throughput Screening Assays, Humans, NIMA-Interacting Peptidylprolyl Isomerase, Neoplasms, Experimental, Protein Binding, Protein Interaction Mapping, Selenium Compounds, Treatment Outcome