Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor
Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor
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DOI：
10.1021/acs.jmedchem.6b00680
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发表时间：
2016-09-08
影响因子：
7.3
通讯作者：
LaMarche, Matthew J.
中科院分区：
文献类型：
--
作者：
Fortanet, Jorge Garcia;Chen, Christine Hiu-Tung;LaMarche, Matthew J.
SHP 2是一种非受体蛋白酪氨酸磷酸酶（PTP），由PTPN 11基因编码，通过MAPK信号通路参与细胞生长和分化。据称，SHP 2在程序性细胞死亡途径（PD-1/PD-L1）中也起重要作用。作为与多种癌症相关疾病相关的癌蛋白以及潜在的免疫调节剂，控制SHP 2活性具有重要的治疗意义。最近在我们的实验室中，一种SHP 2的小分子抑制剂被鉴定为一种变构调节剂，其稳定了SHP 2的自抑制构象。进行高通量筛选以鉴定可进展的化学物质，X射线晶体学揭示了在先前未公开的变构结合口袋中的结合位置。采用基于结构的药物设计来优化SHP 2抑制，并表征了几种新的蛋白质-配体相互作用。这些研究最终发现了6-（4-氨基-4-甲基哌啶-1-基）-3-（2，3-二氯苯基）吡嗪-2-胺（SHP 099，I），一种强效、选择性、口服生物可利用且有效的SHP 2抑制剂。
SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our labs, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the auto-inhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition and several new protein-ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, I), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.