Ahmed Vanessa F, Bottini Nunzio, Barrios Amy M
Department of Medicinal Chemistry, University of Utah, 30 South 2000 East, Salt Lake City, UT 84112 (USA).
ChemMedChem. 2014 Feb;9(2):296-9. doi: 10.1002/cmdc.201300404. Epub 2014 Jan 8.
Covalent inhibitors of lymphoid tyrosine phosphatase (LYP) were identified from a screen of the NIH Molecular Libraries Small Molecules Repository (MLSMR). Both of the two lead compounds identified have phosphotyrosine-mimetic benzoic acid moieties as well as electrophilic acrylonitrile groups. Inhibition kinetics of both compounds are consistent with covalent modification of the enzyme, with nanomolar KI and reciprocal millisecond kinact values, representing the best efficiency ratios (kinact /KI ) among currently reported covalent LYP inhibitors. Covalent inhibitors can provide longer efficacy and better selectivity than more conventional noncovalent inhibitors, and these lead compounds are an important step toward the development of protein tyrosine phosphatase (PTP)-targeted covalent therapeutic compounds.
从美国国立卫生研究院分子文库小分子储存库（MLSMR）的筛选中鉴定出了淋巴细胞酪氨酸磷酸酶（LYP）的共价抑制剂。所鉴定的两种先导化合物均具有磷酸酪氨酸模拟苯甲酸部分以及亲电丙烯腈基团。两种化合物的抑制动力学均与该酶的共价修饰一致，其抑制常数（KI）为纳摩尔级，反应速率常数（kinact）为倒数毫秒级，代表了目前报道的共价LYP抑制剂中最佳的效率比（kinact /KI）。与更传统的非共价抑制剂相比，共价抑制剂可以提供更长的疗效和更好的选择性，并且这些先导化合物是朝着开发靶向蛋白酪氨酸磷酸酶（PTP）的共价治疗化合物迈出的重要一步。
