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

作者：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^*

来源：Journal of Medicinal Chemistry, 2013, 56(12): 4990-5008.

DOI：10.1021/jm400248c

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.

• 出版日期2013-6-27