Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors
Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors
复制标题
DOI：
10.1021/acsmedchemlett.5b00118
复制
发表时间：
2015-07-01
影响因子：
4.2
通讯作者：
Zhang, Zhong-Yin
中科院分区：
文献类型：
--
作者：
He, Rongjun;Yu, Zhi-Hong;Zhang, Zhong-Yin
蛋白酪氨酸磷酸酶(PTPs)是许多疾病的潜在治疗靶点。不幸的是，尽管大量的药物发现工作致力于PTPs，但获得选择性和细胞渗透性的PTP抑制剂仍然具有极大的挑战性。我们描述了一种策略，以探索先前未知的PTP抑制活性的现有药物空间。这导致了头孢素丁作为SHP2的抑制剂被发现，SHP2是PTP家族中的一种致癌磷酸酶。SHP2与头孢菌素相互作用的晶体结构分析确定磺苯乙酰胺(SPAA)是一种新的磷酸酪氨酸(PTyr)模拟物。一种结构导向和基于SPAA片段的聚焦文库方法产生了几种有效的和选择性的SHP2抑制剂。值得注意的是，这些抑制剂阻止了SHP2介导的信号事件和几种癌细胞系的增殖。因此，SPAA可能成为开发其他PTP化学探针的新平台。
Protein tyrosine phosphatases (PTPs) are potential therapeutic targets for many diseases. Unfortunately, despite considerable drug discovery efforts devoted to PTPs, obtaining selective and cell permeable PTP inhibitors remains highly challenging. We describe a strategy to explore the existing drug space for previously unknown PTP inhibitory activities. This led to the discovery of cefsulodin as an inhibitor of SHP2, an oncogenic phosphatase in the PTP family. Crystal structure analysis of SHP2 interaction with cefsulodin identified sulfophenyl acetic amide (SPAA) as a novel phosphotyrosine (pTyr) mimetic. A structure-guided and SPAA fragment-based focused library approach produced several potent and selective SHP2 inhibitors. Notably, these inhibitors blocked SHP2-mediated signaling events and proliferation in several cancer cell lines. Thus, SPAA may serve as a new platform for developing chemical probes for other PTPs.