Lazo John S, McQueeney Kelley E, Sharlow Elizabeth R
Department of Pharmacology, Fiske Drug Discovery Laboratory, University of Virginia, Charlottesville, VA, USA.
SLAS Discov. 2017 Oct;22(9):1071-1083. doi: 10.1177/2472555217721142. Epub 2017 Jul 26.
The drug discovery landscape is littered with promising therapeutic targets that have been abandoned because of insufficient validation, historical screening failures, and inferior chemotypes. Molecular targets once labeled as "undruggable" or "intractable" are now being more carefully interrogated, and while they remain challenging, many target classes are appearing more approachable. Protein tyrosine phosphatases represent an excellent example of a category of molecular targets that have emerged as druggable, with several small molecules and antibodies recently becoming available for further development. In this review, we examine some of the diseases that are associated with protein tyrosine phosphatase dysfunction and use some prototype contemporary strategies to illustrate approaches that are being used to identify small molecules targeting this enzyme class.
药物研发领域充斥着许多有前景的治疗靶点，但由于验证不足、历史筛选失败以及化学类型不佳而被放弃。曾经被标记为“不可成药”或“难处理”的分子靶点现在正受到更仔细的审视，虽然它们仍然具有挑战性，但许多靶点类别似乎更易于攻克。蛋白酪氨酸磷酸酶就是一类已成为可成药分子靶点的绝佳例子，最近有几种小分子和抗体可供进一步开发。在本综述中，我们研究了一些与蛋白酪氨酸磷酸酶功能障碍相关的疾病，并使用一些当代原型策略来说明用于识别靶向这类酶的小分子的方法。
