An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol

Taoda Shi; E. M. Kithsiri Wijeratne; Cristian Solano; Andrew J. Ambrose; Alison B. Ross; Charles Norwood; Charles K. Orido; Tigran Grigoryan; Joseph Tillotson; Minjin Kang; Gang Luo; Bradley M. Keegan; Wenhao Hu; Brian S.J. Blagg; Donna D. Zhang; A. A. Leslie Gunatilaka; Eli Chapman

doi:10.1021/acs.biochem.9b00499

An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol

Taoda Shi, E. M. Kithsiri Wijeratne, Cristian Solano, Andrew J. Ambrose, Alison B. Ross, Charles Norwood, Charles K. Orido, Tigran Grigoryan, Joseph Tillotson, Minjin Kang, Gang Luo, Bradley M. Keegan, Wenhao Hu, Brian S.J. Blagg, Donna D. Zhang, A. A. Leslie Gunatilaka, Eli Chapman

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Abstract

A library of natural products and their derivatives was screened for inhibition of protein tyrosine phosphatase (PTP) 1B, which is a validated drug target for the treatment of obesity and type II diabetes. Of those active in the preliminary assay, the most promising was compound 2 containing a novel pyrrolopyrazoloisoquinolone scaffold derived by treating radicicol (1) with hydrazine. This nitrogen-atom augmented radicicol derivative was found to be PTP1B selective relative to other highly homologous nonreceptor PTPs. Biochemical evaluation, molecular docking, and mutagenesis revealed 2 to be an allosteric inhibitor of PTP1B with a submicromolar K_i. Cellular analyses using C2C12 myoblasts indicated that 2 restored insulin signaling and increased glucose uptake.

Original language	English (US)
Pages (from-to)	3225-3231
Number of pages	7
Journal	Biochemistry
Volume	58
Issue number	30
DOIs	https://doi.org/10.1021/acs.biochem.9b00499
State	Published - Jul 30 2019

ASJC Scopus subject areas

Biochemistry

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10.1021/acs.biochem.9b00499

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Shi, T., Kithsiri Wijeratne, E. M., Solano, C., Ambrose, A. J., Ross, A. B., Norwood, C., Orido, C. K., Grigoryan, T., Tillotson, J., Kang, M., Luo, G., Keegan, B. M., Hu, W., Blagg, B. S. J., Zhang, D. D., Leslie Gunatilaka, A. A., & Chapman, E. (2019). An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol. Biochemistry, 58(30), 3225-3231. https://doi.org/10.1021/acs.biochem.9b00499

Shi, T, Kithsiri Wijeratne, EM, Solano, C, Ambrose, AJ, Ross, AB, Norwood, C, Orido, CK, Grigoryan, T, Tillotson, J, Kang, M, Luo, G, Keegan, BM, Hu, W, Blagg, BSJ, Zhang, DD , Leslie Gunatilaka, AA & Chapman, E 2019, 'An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol', Biochemistry, vol. 58, no. 30, pp. 3225-3231. https://doi.org/10.1021/acs.biochem.9b00499

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title = "An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol",

abstract = "A library of natural products and their derivatives was screened for inhibition of protein tyrosine phosphatase (PTP) 1B, which is a validated drug target for the treatment of obesity and type II diabetes. Of those active in the preliminary assay, the most promising was compound 2 containing a novel pyrrolopyrazoloisoquinolone scaffold derived by treating radicicol (1) with hydrazine. This nitrogen-atom augmented radicicol derivative was found to be PTP1B selective relative to other highly homologous nonreceptor PTPs. Biochemical evaluation, molecular docking, and mutagenesis revealed 2 to be an allosteric inhibitor of PTP1B with a submicromolar Ki. Cellular analyses using C2C12 myoblasts indicated that 2 restored insulin signaling and increased glucose uptake.",

author = "Taoda Shi and {Kithsiri Wijeratne}, {E. M.} and Cristian Solano and Ambrose, {Andrew J.} and Ross, {Alison B.} and Charles Norwood and Orido, {Charles K.} and Tigran Grigoryan and Joseph Tillotson and Minjin Kang and Gang Luo and Keegan, {Bradley M.} and Wenhao Hu and Blagg, {Brian S.J.} and Zhang, {Donna D.} and {Leslie Gunatilaka}, {A. A.} and Eli Chapman",

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doi = "10.1021/acs.biochem.9b00499",

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AU - Ambrose, Andrew J.

AU - Ross, Alison B.

AU - Norwood, Charles

AU - Orido, Charles K.

AU - Grigoryan, Tigran

AU - Tillotson, Joseph

AU - Kang, Minjin

AU - Luo, Gang

AU - Keegan, Bradley M.

AU - Hu, Wenhao

AU - Blagg, Brian S.J.

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AU - Chapman, Eli

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AB - A library of natural products and their derivatives was screened for inhibition of protein tyrosine phosphatase (PTP) 1B, which is a validated drug target for the treatment of obesity and type II diabetes. Of those active in the preliminary assay, the most promising was compound 2 containing a novel pyrrolopyrazoloisoquinolone scaffold derived by treating radicicol (1) with hydrazine. This nitrogen-atom augmented radicicol derivative was found to be PTP1B selective relative to other highly homologous nonreceptor PTPs. Biochemical evaluation, molecular docking, and mutagenesis revealed 2 to be an allosteric inhibitor of PTP1B with a submicromolar Ki. Cellular analyses using C2C12 myoblasts indicated that 2 restored insulin signaling and increased glucose uptake.

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An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol

Abstract

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CCDC 1880627: Experimental Crystal Structure Determination

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An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol

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CCDC 1880627: Experimental Crystal Structure Determination

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