title: A potent and selective small-molecule inhibitor for the lymphoid-specific tyrosine phosphatase (LYP), a target associated with autoimmune diseases.
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 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA.
authors.forename: Yantao
authors.initials: Y
authors.lastname: He
authors.forename: Sijiu
authors.initials: S
authors.lastname: Liu
authors.forename: Ambili
authors.initials: A
authors.lastname: Menon
authors.forename: Stephanie
authors.initials: S
authors.lastname: Stanford
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Oppong
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Gunawan
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Wu
authors.forename: Amy M
authors.initials: AM
authors.lastname: Barrios
authors.forename: Nunzio
authors.initials: N
authors.lastname: Bottini
authors.forename: Andrew C B
authors.initials: AC
authors.lastname: Cato
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
mesh_terms: D000707:Anaphylaxis / Q000188:drug therapy; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy*; D002264:Carboxylic Acids / Q000737:chemistry; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002264:Carboxylic Acids; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D011505:Protein-Tyrosine Kinases