He, YantaoLiu, SijiuMenon, AmbiliStanford, StephanieOppong, EmmanuelGunawan, Andrea M.Wu, LiWu, Dennis J.Barrios, Amy M.Bottini, NunzioCato, Andrew C. B.Zhang, Zhong-Yin2025-05-082025-05-082013He Y, Liu S, Menon A, et al. A potent and selective small-molecule inhibitor for the lymphoid-specific tyrosine phosphatase (LYP), a target associated with autoimmune diseases. J Med Chem. 2013;56(12):4990-5008. doi:10.1021/jm400248chttps://hdl.handle.net/1805/47878Lymphoid-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 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.en-USPublisher PolicyProtein kinase inhibitorsLymphocyte activationCarboxylic acidsJurkat cellsMast cellsArticle