A potent and selective small-molecule inhibitor for the lymphoid-specific tyrosine phosphatase (LYP), a target associated with autoimmune diseases

Yantao He, Sijiu Liu, Ambili Menon, Stephanie Stanford, Emmanuel Oppong, Andrea M. Gunawan, Li Wu, Dennis J. Wu, Amy M. Barrios, Nunzio Bottini, Andrew C B Cato, Zhong-Yin Zhang

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Lymphoid-specific tyrosine phosphatase (LYP), a member of the protein tyrosine phosphatase (PTP) family of signaling enzymes, is associated with a broad spectrum of autoimmune diseases. Herein we describe our structure-based lead optimization efforts within a 6-hydroxy-benzofuran-5-carboxylic acid series culminating in the identification of compound 8b, a potent and selective inhibitor of LYP with a Ki value of 110 nM and more than 9-fold selectivity over a large panel of PTPs. The structure of LYP in complex with 8b was obtained by X-ray crystallography, providing detailed information about the molecular recognition of small-molecule ligands binding LYP. Importantly, compound 8b possesses highly efficacious cellular activity in both T- and mast cells and is capable of blocking anaphylaxis in mice. Discovery of 8b establishes a starting point for the development of clinically useful LYP inhibitors for treating a wide range of autoimmune disorders.

Original languageEnglish
Pages (from-to)4990-5008
Number of pages19
JournalJournal of Medicinal Chemistry
Volume56
Issue number12
DOIs
StatePublished - Jun 27 2013

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Phosphoric Monoester Hydrolases
Autoimmune Diseases
Tyrosine
Protein Tyrosine Phosphatases
X Ray Crystallography
Anaphylaxis
Carboxylic Acids
Mast Cells
Ligands
T-Lymphocytes
Enzymes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

A potent and selective small-molecule inhibitor for the lymphoid-specific tyrosine phosphatase (LYP), a target associated with autoimmune diseases. / He, Yantao; Liu, Sijiu; Menon, Ambili; Stanford, Stephanie; Oppong, Emmanuel; Gunawan, Andrea M.; Wu, Li; Wu, Dennis J.; Barrios, Amy M.; Bottini, Nunzio; Cato, Andrew C B; Zhang, Zhong-Yin.

In: Journal of Medicinal Chemistry, Vol. 56, No. 12, 27.06.2013, p. 4990-5008.

Research output: Contribution to journalArticle

He, Y, Liu, S, Menon, A, Stanford, S, Oppong, E, Gunawan, AM, Wu, L, Wu, DJ, Barrios, AM, Bottini, N, Cato, ACB & Zhang, Z-Y 2013, 'A potent and selective small-molecule inhibitor for the lymphoid-specific tyrosine phosphatase (LYP), a target associated with autoimmune diseases', Journal of Medicinal Chemistry, vol. 56, no. 12, pp. 4990-5008. https://doi.org/10.1021/jm400248c
He, Yantao ; Liu, Sijiu ; Menon, Ambili ; Stanford, Stephanie ; Oppong, Emmanuel ; Gunawan, Andrea M. ; Wu, Li ; Wu, Dennis J. ; Barrios, Amy M. ; Bottini, Nunzio ; Cato, Andrew C B ; Zhang, Zhong-Yin. / A potent and selective small-molecule inhibitor for the lymphoid-specific tyrosine phosphatase (LYP), a target associated with autoimmune diseases. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 12. pp. 4990-5008.
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AU - Stanford, Stephanie

AU - Oppong, Emmanuel

AU - Gunawan, Andrea M.

AU - Wu, Li

AU - Wu, Dennis J.

AU - Barrios, Amy M.

AU - Bottini, Nunzio

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AU - Zhang, Zhong-Yin

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