Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, Indiana 46202, USA.
J Med Chem. 2013 Jun 27;56(12):4990-5008. doi: 10.1021/jm400248c. Epub 2013 Jun 6.
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.
淋巴特异性酪氨酸磷酸酶（LYP）是蛋白酪氨酸磷酸酶（PTP）家族信号酶中的一员，与多种自身免疫性疾病相关。本文描述了我们在 6-羟基苯并呋喃-5-羧酸系列中的基于结构的先导化合物优化工作，最终确定了化合物 8b，它是一种有效的 LYP 选择性抑制剂，其 K(i)值为 110 nM，对一组大型 PTP 具有超过 9 倍的选择性。通过 X 射线晶体学获得了 LYP 与 8b 复合物的结构，提供了有关小分子配体与 LYP 结合的分子识别的详细信息。重要的是，化合物 8b 在 T 细胞和肥大细胞中具有高效的细胞活性，并且能够阻止小鼠过敏反应。8b 的发现为开发用于治疗广泛自身免疫性疾病的临床有用的 LYP 抑制剂奠定了基础。
