A dual inhibitor against prolyl isomerase Pin1 and cyclophilin discovered by a novel real-time fluorescence detection method

Tadashi Mori, Masafumi Hidaka, Yi Chin Lin, Ibuki Yoshizawa, Takayoshi Okabe, Shinichiro Egashira, Hirotatsu Kojima, Tetsuo Nagano, Mamoru Koketsu, Mari Takamiya, Takafumi Uchida

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28 Citations (Scopus)

Abstract

Pin1, a peptidyl prolyl cis/trans isomerase (PPIase), is a potential target molecule for cancer, infectious disease, and Alzheimer's disease. We established a high-throughput screening method for Pin1 inhibitors, which employs a real-time fluorescence detector. This screening method identified 66 compounds that inhibit Pin1 out of 9756 compounds from structurally diverse chemical libraries. Further evaluations of surface plasmon resonance methods and a cell proliferation assay were performed. We discovered a cell-active inhibitor, TME-001 (2-(3-chloro-4-fluoro-phenyl)-isothiazol-3-one). Surprisingly, kinetic analyses revealed that TME-001 is the first compound that exhibits dual inhibition of Pin1 (IC50=6.1μM) and cyclophilin, another type of PPIase, (IC50=13.7μM). This compound does not inhibit FKBP. This finding suggests the existence of similarities of structure and reaction mechanism between Pin1 and cyclophilin, and may lead to a more complete understanding of the active sites of PPIases.

Original languageEnglish
Pages (from-to)439-443
Number of pages5
JournalBiochemical and biophysical research communications
Volume406
Issue number3
DOIs
Publication statusPublished - 2011 Mar 18

Keywords

  • Cyclophilin
  • Docking studies
  • High-throughput screening
  • Inhibitor
  • Peptidyl prolyl cis/trans isomerase
  • Pin1

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Mori, T., Hidaka, M., Lin, Y. C., Yoshizawa, I., Okabe, T., Egashira, S., Kojima, H., Nagano, T., Koketsu, M., Takamiya, M., & Uchida, T. (2011). A dual inhibitor against prolyl isomerase Pin1 and cyclophilin discovered by a novel real-time fluorescence detection method. Biochemical and biophysical research communications, 406(3), 439-443. https://doi.org/10.1016/j.bbrc.2011.02.066