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

doi:10.1016/j.bbrc.2011.02.066

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

AGR - Agricultural Chemistry

Research output: Contribution to journal › Article › peer-review

32 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 language	English
Pages (from-to)	439-443
Number of pages	5
Journal	Biochemical and biophysical research communications
Volume	406
Issue number	3
DOIs	https://doi.org/10.1016/j.bbrc.2011.02.066
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbrc.2011.02.066

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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

Mori, T, Hidaka, M, Lin, YC, 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, vol. 406, no. 3, pp. 439-443. https://doi.org/10.1016/j.bbrc.2011.02.066

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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.",

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AU - Egashira, Shinichiro

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AU - Takamiya, Mari

AU - Uchida, Takafumi

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N2 - 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.

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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