苯氧乙酸对造血蛋白酪氨酸磷酸酶的抑制作用。
Inhibition of the Hematopoietic Protein Tyrosine Phosphatase by Phenoxyacetic Acids.
作者信息
Bobkova Ekaterina V, Liu Wallace H, Colayco Sharon, Rascon Justin, Vasile Stefan, Gasior Carlton, Critton David A, Chan Xochella, Dahl Russell, Su Ying, Sergienko Eduard, Chung Thomas D Y, Mustelin Tomas, Page Rebecca, Tautz Lutz
机构信息
Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
出版信息
ACS Med Chem Lett. 2011 Feb;2(2):113-118. doi: 10.1021/ml100103p.
Protein tyrosine phosphatases (PTPs) have only recently become the focus of attention in the search for novel drug targets despite the fact that they play vital roles in numerous cellular processes and are implicated in many human diseases. The hematopoietic protein tyrosine phosphatase (HePTP) is often found dysregulated in preleukemic myelodysplastic syndrome (MDS), as well as in acute myelogenous leukemia (AML). Physiological substrates of HePTP include the mitogen-activated protein kinases (MAPKs) ERK1/2 and p38. Specific modulators of HePTP catalytic activity will be useful for elucidating mechanisms of MAPK regulation in hematopietic cells, and may also provide treatments for hematopoietic malignancies such as AML. Here we report the discovery of phenoxyacetic acids as inhibitors of HePTP. Structure-activity relationship (SAR) analysis and in silico docking studies reveal the molecular basis of HePTP inhibition by these compounds. We also show that these compounds are able to penetrate cell membranes and inhibit HePTP in human T lymphocytes.
尽管蛋白质酪氨酸磷酸酶（PTPs）在众多细胞过程中发挥着至关重要的作用，并与许多人类疾病有关，但直到最近它们才成为寻找新型药物靶点的关注焦点。造血蛋白酪氨酸磷酸酶（HePTP）在白血病前期骨髓增生异常综合征（MDS）以及急性髓性白血病（AML）中经常出现失调。HePTP的生理底物包括丝裂原活化蛋白激酶（MAPKs）ERK1/2和p38。HePTP催化活性的特异性调节剂将有助于阐明造血细胞中MAPK调节的机制，也可能为AML等造血系统恶性肿瘤提供治疗方法。在此，我们报告发现苯氧乙酸作为HePTP的抑制剂。构效关系（SAR）分析和计算机模拟对接研究揭示了这些化合物抑制HePTP的分子基础。我们还表明，这些化合物能够穿透细胞膜并在人T淋巴细胞中抑制HePTP。
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