2-thiazolylimino/heteroarylimino-5-arylidene-4-thiazolidinones as new agents with SHP-2 inhibitory action
2-thiazolylimino/heteroarylimino-5-arylidene-4-thiazolidinones as new agents with SHP-2 inhibitory action
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DOI：
10.1021/jm8004306
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发表时间：
2008-09-11
影响因子：
7.3
通讯作者：
Saxena, A. K.
中科院分区：
文献类型：
--
作者：
Geronikaki, A.;Eleftheriou, P.;Saxena, A. K.
SHP-2是一种由PTPN 11基因编码的非受体蛋白酪氨酸磷酸酶，通过RAS/MAP激酶途径介导生长因子和细胞因子的细胞信号传导。PTPN 11基因的体细胞突变约占青少年粒单核细胞白血病（JMML）患者的18%。此外，在超过50%的努南综合征患者中发现了导致持续活性酶的SHP-2突变，并认为这是这些患者患青少年白血病和其他癌症类型的高趋势的原因。近年来，SHP-2成为一个新的药物靶点，但迄今为止这方面的研究还很少。在本研究中，172-噻唑亚氨基/杂芳基亚氨基-5-亚芳基-4-噻唑烷酮分为三个系列的衍生物轴承噻唑-，苯并[d]噻唑-，苯并[d]异噻唑环的SHP-2抑制活性进行了测试。大部分化合物为良好的SHP-2抑制剂。苯并[d]噻唑类化合物的抑菌效果最好。对接研究表明，疏水相互作用和氢键的形成稳定酶抑制剂复合物。
SHP-2, a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene, mediates cell signaling by growth factors and cytokines via the RAS/MAP kinase pathway. Somatic mutations in PTPN11 gene account for approximately 18% of juvenile myelomonocytic leukemia (JMML) patients. Moreover, SHP-2 mutations leading to continuously active enzyme were found in more than 50% of Noonan syndrome patients and are considered to be responsible for the high tendency of these patients to juvenile leukemias and other cancer types. Recently SHP-2 became a new drug target, but till flow little has been done in this field. In the present study, 172-thiazolylimino/heteroarylimino-5-arylidene-4-thiazolidinones divided into three series of derivatives bearing thiazole-, benzo[d]thiazole-, and benzo[d]isothizole rings were tested for SHP-2 inhibitory activity. Most of the compounds were good SHP-2 inhibitors. Benzo[d]thiazole derivatives exhibited the best inhibitory action. Docking studies revealed that hydrophobic interactions and hydrogen bond formation stabilize enzyme-inhibitor complex.