A Potent and Selective Small-Molecule Inhibitor for the Lymphoid-Specific Tyrosine Phosphatase (LYP), a Target Associated with Autoimmune Diseases

Journal article


Research Areas

Publication Details

Author list: He YT, Liu SJ, Menon A, Stanford S, Oppong E, Gunawan AM, Wu L, Wu DJ, Barrios AM, Bottini N, Cato ACB, Zhang ZY
Publisher: American Chemical Society
Publication year: 2013
Volume number: 56
Issue number: 12
Start page: 4990
End page: 5008
Number of pages: 19
ISSN: 0022-2623
Languages: English-Great Britain (EN-GB)


Lymphoid-specific tyrosine phosphatase (LIP), 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 K-i 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.




No matching items found.

Last updated on 2019-23-08 at 11:15