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

42 Scopus citations

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    He, Y., Liu, S., Menon, A., Stanford, S., Oppong, E., Gunawan, A. M., Wu, L., Wu, D. J., Barrios, A. M., Bottini, N., Cato, A. C. B., & 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, 56(12), 4990-5008. https://doi.org/10.1021/jm400248c