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 Zhang, Leslie Gunatilaka, Eli Chapman

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3225-3231
Number of pages7
JournalBiochemistry
Volume58
Issue number30
DOIs
StatePublished - Jul 30 2019

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hydrazine
Protein Isoforms
Nitrogen
Non-Receptor Type 1 Protein Tyrosine Phosphatase
Derivatives
Atoms
Mutagenesis
Myoblasts
Medical problems
Biological Products
Scaffolds
Type 2 Diabetes Mellitus
Assays
Obesity
Insulin
Glucose
Pharmaceutical Preparations
monorden

ASJC Scopus subject areas

  • Biochemistry

Cite this

Shi, T., Kithsiri Wijeratne, E. M., Solano, C., Ambrose, A. J., Ross, A. B., Norwood, C., ... 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

An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol. / Shi, Taoda; Kithsiri Wijeratne, E. M.; Solano, Cristian; Ambrose, Andrew J.; Ross, Alison B.; Norwood, Charles; Orido, Charles K.; Grigoryan, Tigran; Tillotson, Joseph; Kang, Minjin; Luo, Gang; Keegan, Bradley M.; Hu, Wenhao; Blagg, Brian S.J.; Zhang, Donna; Gunatilaka, Leslie; Chapman, Eli.

In: Biochemistry, Vol. 58, No. 30, 30.07.2019, p. 3225-3231.

Research output: Contribution to journalArticle

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, D, Gunatilaka, L & 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
Shi T, Kithsiri Wijeratne EM, Solano C, Ambrose AJ, Ross AB, Norwood C et al. An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol. Biochemistry. 2019 Jul 30;58(30):3225-3231. https://doi.org/10.1021/acs.biochem.9b00499
Shi, Taoda ; Kithsiri Wijeratne, E. M. ; Solano, Cristian ; Ambrose, Andrew J. ; Ross, Alison B. ; Norwood, Charles ; Orido, Charles K. ; Grigoryan, Tigran ; Tillotson, Joseph ; Kang, Minjin ; Luo, Gang ; Keegan, Bradley M. ; Hu, Wenhao ; Blagg, Brian S.J. ; Zhang, Donna ; Gunatilaka, Leslie ; Chapman, Eli. / An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol. In: Biochemistry. 2019 ; Vol. 58, No. 30. pp. 3225-3231.
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