Discovery of novel selenium derivatives as Pin1 inhibitors by high-throughput screening.
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.
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.
Amit
A
Subedi
Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan.
Takeshi
T
Shimizu
Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Kanagawa, 236-0004, Japan.
Akihide
A
Ryo
Bio-Active Compounds Discovery Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan.
Emiko
E
Sanada
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.
Nobumoto
N
Watanabe
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: hisyo@riken.jp.
Hiroyuki
H
Osada
D001665:Binding Sites; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods; D018036:Selenium Compounds / Q000737:chemistry* / Q000627:therapeutic use*; D016896:Treatment Outcome
D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D018036:Selenium Compounds
Cancer; High-throughput screening; PPIase; Pin1; Selenium