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首页> 外文期刊>Journal of Medicinal Chemistry >Therapeutic Potential of Targeting the Oncogenic SHP2 Phosphatase
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Therapeutic Potential of Targeting the Oncogenic SHP2 Phosphatase

机译：靶向致癌SHP2磷酸酶的治疗潜力

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摘要

The Src homology 2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase associated with various kinds of leukemia and solid tumors. Thus, there is substantial interest in developing SHP2 inhibitors as potential anticancer and antileukemia agents. Using a structure-guided and fragment-based library approach, we identified a novel hydroxyindole carboxylic acid-based SHP2 inhibitor 11a-1, with an IC_(50) value of 200 nM and greater than 5-fold selectivity against 20 mammalian PTPs. Structural and modeling studies reveal that the hydroxyindole carboxylic acid anchors the inhibitor to the SHP2 active site, while interactions of the oxalamide linker and the phenylthiophene tail with residues in the β_5-β6_ loop contribute to 11a-1's binding potency and selectivity. Evidence suggests that 11a-1 specifically attenuates the SHP2-dependent signaling inside the cell. Moreover, 11a-1 blocks growth factor mediated Erk1/2 and Akt activation and exhibits excellent antiproliferative activity in lung cancer and breast cancer as well as leukemia cell lines.
机译：包含蛋白酪氨酸磷酸酶2（SHP2）的Src同源2域是与多种白血病和实体瘤相关的致癌磷酸酶。因此，人们对开发SHP2抑制剂作为潜在的抗癌和抗白血病药具有极大的兴趣。使用结构指导和基于片段的文库方法，我们确定了一种新型的基于羟基吲哚羧酸的SHP2抑制剂11a-1，其IC_（50）值为200 nM，对20种哺乳动物PTP的选择性大于5倍。结构和模型研究表明，羟基吲哚羧酸将抑制剂锚定在SHP2活性位点上，而草酰胺键和苯噻吩尾与β_5-β6_环中残基的相互作用有助于11a-1的结合力和选择性。有证据表明11a-1会特异性减弱细胞内SHP2依赖性信号传导。此外，11a-1阻断了生长因子介导的Erk1 / 2和Akt活化，并在肺癌，乳腺癌以及白血病细胞系中表现出出色的抗增殖活性。

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