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Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-07-12 00:00:00 , DOI: 10.1021/acs.jmedchem.6b00680 Jorge Garcia Fortanet 1 , Christine Hiu-Tung Chen 1 , Ying-Nan P. Chen 1 , Zhouliang Chen 1 , Zhan Deng 1 , Brant Firestone 1 , Peter Fekkes 1 , Michelle Fodor 1 , Pascal D. Fortin 1 , Cary Fridrich 1 , Denise Grunenfelder 1 , Samuel Ho 1 , Zhao B. Kang 1 , Rajesh Karki 1 , Mitsunori Kato 1 , Nick Keen 1 , Laura R. LaBonte 1 , Jay Larrow 1 , Francois Lenoir 1 , Gang Liu 1 , Shumei Liu 1 , Franco Lombardo 1 , Dyuti Majumdar 1 , Matthew J. Meyer 1 , Mark Palermo 1 , Lawrence Perez 1 , Minying Pu 1 , Timothy Ramsey 1 , William R. Sellers 1 , Michael D. Shultz 1 , Travis Stams 1 , Christopher Towler 1 , Ping Wang 1 , Sarah L. Williams 1 , Ji-Hu Zhang 1 , Matthew J. LaMarche 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-07-12 00:00:00 , DOI: 10.1021/acs.jmedchem.6b00680 Jorge Garcia Fortanet 1 , Christine Hiu-Tung Chen 1 , Ying-Nan P. Chen 1 , Zhouliang Chen 1 , Zhan Deng 1 , Brant Firestone 1 , Peter Fekkes 1 , Michelle Fodor 1 , Pascal D. Fortin 1 , Cary Fridrich 1 , Denise Grunenfelder 1 , Samuel Ho 1 , Zhao B. Kang 1 , Rajesh Karki 1 , Mitsunori Kato 1 , Nick Keen 1 , Laura R. LaBonte 1 , Jay Larrow 1 , Francois Lenoir 1 , Gang Liu 1 , Shumei Liu 1 , Franco Lombardo 1 , Dyuti Majumdar 1 , Matthew J. Meyer 1 , Mark Palermo 1 , Lawrence Perez 1 , Minying Pu 1 , Timothy Ramsey 1 , William R. Sellers 1 , Michael D. Shultz 1 , Travis Stams 1 , Christopher Towler 1 , Ping Wang 1 , Sarah L. Williams 1 , Ji-Hu Zhang 1 , Matthew J. LaMarche 1
Affiliation
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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 programmed cell death pathway (PD-1/PD-L1). Because it is 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 laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited 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, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.
中文翻译：
SHP2的变构抑制：一种有效的，选择性的和口服有效的磷酸酶抑制剂的鉴定。
SHP2是由PTPN11编码的非受体蛋白酪氨酸磷酸酶（PTP）该基因通过MAPK信号通路参与细胞生长和分化。据称SHP2在程序性细胞死亡途径（PD-1 / PD-L1）中也起着重要作用。由于它是一种与多种癌症相关疾病相关的癌蛋白，也是一种潜在的免疫调节剂，因此控制SHP2活性具有重要的治疗意义。最近在我们的实验室中，SHP2的小分子抑制剂被确定为稳定SHP2自抑制构象的变构调节剂。进行了高通量筛选，以鉴定可进展的化学物质，并且X射线晶体学揭示了在以前未公开的变构结合口袋中的结合位置。基于结构的药物设计被用于优化SHP2抑制，并表征了几种新的蛋白质-配体相互作用。1），一种有效的，选择性的，口服生物利用的，有效的SHP2抑制剂。
更新日期：2016-07-12
中文翻译：
SHP2的变构抑制：一种有效的，选择性的和口服有效的磷酸酶抑制剂的鉴定。
SHP2是由PTPN11编码的非受体蛋白酪氨酸磷酸酶（PTP）该基因通过MAPK信号通路参与细胞生长和分化。据称SHP2在程序性细胞死亡途径（PD-1 / PD-L1）中也起着重要作用。由于它是一种与多种癌症相关疾病相关的癌蛋白，也是一种潜在的免疫调节剂，因此控制SHP2活性具有重要的治疗意义。最近在我们的实验室中，SHP2的小分子抑制剂被确定为稳定SHP2自抑制构象的变构调节剂。进行了高通量筛选，以鉴定可进展的化学物质，并且X射线晶体学揭示了在以前未公开的变构结合口袋中的结合位置。基于结构的药物设计被用于优化SHP2抑制，并表征了几种新的蛋白质-配体相互作用。1），一种有效的，选择性的，口服生物利用的，有效的SHP2抑制剂。
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