Discovery and characterisation of hydrazines as inhibitors of the immune suppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1)

Sai Parng S Fung; Haiyan Wang; Petr Tomek; Christopher J. Squire; Jack U. Flanagan; Brian D. Palmer; David J A Bridewell; Sofian M. Tijono; Joanne F. Jamie; Lai Ming Ching

doi:10.1016/j.bmc.2013.10.037

Discovery and characterisation of hydrazines as inhibitors of the immune suppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1)

Sai Parng S Fung, Haiyan Wang, Petr Tomek, Christopher J. Squire, Jack U. Flanagan, Brian D. Palmer, David J A Bridewell, Sofian M. Tijono, Joanne F. Jamie, Lai Ming Ching^*

^*Corresponding author for this work

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

27 Citations (Scopus)

Abstract

Screening of a fragment library identified 2-hydrazinobenzothiazole as a potent inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme expressed by tumours that suppresses the immune system. Spectroscopic studies indicated that 2-hydrazinobenzothiazole interacted with the IDO1 haem and in silico docking predicted that the interaction was through hydrazine. Subsequent studies of hydrazine derivatives identified phenylhydrazine (IC₅₀ = 0.25 ± 0.07 μM) to be 32-fold more potent than 2-hydrazinobenzothiazole (IC₅₀ = 8.0 ± 2.3 μM) in inhibiting rhIDO1 and that it inhibited cellular IDO1 at concentrations that were noncytotoxic to cells. Here, phenylhydrazine is shown to inhibit IDO1 through binding to haem.

Original language	English
Pages (from-to)	7595-7603
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry
Volume	21
Issue number	24
DOIs	https://doi.org/10.1016/j.bmc.2013.10.037
Publication status	Published - 15 Dec 2013

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Fung, S. P. S., Wang, H., Tomek, P., Squire, C. J., Flanagan, J. U., Palmer, B. D., Bridewell, D. J. A., Tijono, S. M., Jamie, J. F., & Ching, L. M. (2013). Discovery and characterisation of hydrazines as inhibitors of the immune suppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1). Bioorganic and Medicinal Chemistry, 21(24), 7595-7603. https://doi.org/10.1016/j.bmc.2013.10.037

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abstract = "Screening of a fragment library identified 2-hydrazinobenzothiazole as a potent inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme expressed by tumours that suppresses the immune system. Spectroscopic studies indicated that 2-hydrazinobenzothiazole interacted with the IDO1 haem and in silico docking predicted that the interaction was through hydrazine. Subsequent studies of hydrazine derivatives identified phenylhydrazine (IC50 = 0.25 ± 0.07 μM) to be 32-fold more potent than 2-hydrazinobenzothiazole (IC50 = 8.0 ± 2.3 μM) in inhibiting rhIDO1 and that it inhibited cellular IDO1 at concentrations that were noncytotoxic to cells. Here, phenylhydrazine is shown to inhibit IDO1 through binding to haem.",

author = "Fung, {Sai Parng S} and Haiyan Wang and Petr Tomek and Squire, {Christopher J.} and Flanagan, {Jack U.} and Palmer, {Brian D.} and Bridewell, {David J A} and Tijono, {Sofian M.} and Jamie, {Joanne F.} and Ching, {Lai Ming}",

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AU - Fung, Sai Parng S

AU - Wang, Haiyan

AU - Tomek, Petr

AU - Squire, Christopher J.

AU - Flanagan, Jack U.

AU - Palmer, Brian D.

AU - Bridewell, David J A

AU - Tijono, Sofian M.

AU - Jamie, Joanne F.

AU - Ching, Lai Ming

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AB - Screening of a fragment library identified 2-hydrazinobenzothiazole as a potent inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme expressed by tumours that suppresses the immune system. Spectroscopic studies indicated that 2-hydrazinobenzothiazole interacted with the IDO1 haem and in silico docking predicted that the interaction was through hydrazine. Subsequent studies of hydrazine derivatives identified phenylhydrazine (IC50 = 0.25 ± 0.07 μM) to be 32-fold more potent than 2-hydrazinobenzothiazole (IC50 = 8.0 ± 2.3 μM) in inhibiting rhIDO1 and that it inhibited cellular IDO1 at concentrations that were noncytotoxic to cells. Here, phenylhydrazine is shown to inhibit IDO1 through binding to haem.

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ER -

Discovery and characterisation of hydrazines as inhibitors of the immune suppressive enzyme, indoleamine 2,3-dioxygenase 1 (IDO1)

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