Inhibition of hematopoietic protein tyrosine phosphatase augments and prolongs ERK1/2 and p38 activation.
Inhibition of hematopoietic protein tyrosine phosphatase augments and prolongs ERK1/2 and p38 activation.
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DOI：
10.1021/cb2004274
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发表时间：
2012-02-17
影响因子：
4
通讯作者：
Tautz, Lutz
中科院分区：
文献类型：
--
作者：
Sergienko, Eduard;Xu, Jian;Liu, Wallace H.;Dahl, Russell;Critton, David A.;Su, Ying;Brown, Brock T.;Chan, Xochella;Yang, Li;Bobkova, Ekaterina V.;Vasile, Stefan;Yuan, Hongbin;Rascon, Justin;Colayco, Sharon;Sidique, Shyama;Cosford, Nicholas D. P.;Chung, Thomas D. Y.;Mustelin, Tomas;Page, Rebecca;Lombroso, Paul J.;Tautz, Lutz
造血蛋白酪氨酸磷酸酶(HePTP)通过负性调节丝裂原活化蛋白激酶(MAPKs)ERK1/2和p38参与血癌的发生发展。HePTP活性的小分子调节剂可能成为治疗T细胞急性淋巴细胞白血病(T-ALL)和急性髓系白血病(AML)等血液系统恶性肿瘤的有价值的药物。此外，这些化合物将进一步阐明MAPKs在造血细胞中的调控。尽管MAPKs的瞬时激活对生长和增殖至关重要，但这些重要信号分子的长期激活会诱导分化、细胞周期停滞、细胞衰老和细胞凋亡。特定的HePTP抑制剂可能促进后者，从而可能阻止癌细胞的生长。在这里，我们报告了一种小分子的开发，它可以增强人类T细胞中ERK1/2和p38的激活，特别是通过抑制HePTP。在电子对接研究和诱变实验中的构效关系分析揭示了该抑制剂是如何通过与高度保守的催化口袋外围的独特氨基酸残基相互作用来实现对相关磷酸酶的选择性的。重要的是，我们利用这种化合物来证明药物抑制HePTP不仅增加，而且延长了ERK1/2，特别是p38的激活。此外，我们在小鼠的白细胞中表现出了类似的效应，小鼠在低剂量的腹膜腔内注射该抑制剂，剂量为3毫克/公斤。我们的结果保证了未来对这种探测化合物的研究，可能会建立HePTP作为治疗急性白血病的新药靶点。
The hematopoietic protein tyrosine phosphatase (HePTP) is implicated in the development of blood cancers through its ability to negatively regulate the mitogen-activated protein kinases (MAPKs) ERK1/2 and p38. Small-molecule modulators of HePTP activity may become valuable in treating hematopoietic malignancies such as T cell acute lymphoblastic leukemia (T-ALL) and acute myelogenous leukemia (AML). Moreover, such compounds will further elucidate the regulation of MAPKs in hematopoietic cells. Although transient activation of MAPKs is crucial for growth and proliferation, prolonged activation of these important signaling molecules induces differentiation, cell cycle arrest, cell senescence, and apoptosis. Specific HePTP inhibitors may promote the latter and thereby may halt the growth of cancer cells. Here, we report the development of a small molecule that augments ERK1/2 and p38 activation in human T cells, specifically by inhibiting HePTP. Structure-activity relationship analysis, in silico docking studies, and mutagenesis experiments reveal how the inhibitor achieves selectivity for HePTP over related phosphatases by interacting with unique amino acid residues in the periphery of the highly conserved catalytic pocket. Importantly, we utilize this compound to show that pharmacological inhibition of HePTP not only augments, but also prolongs activation of ERK1/2 and, especially, p38. Moreover, we present similar effects in leukocytes from mice intraperitoneally injected with the inhibitor at doses as low as 3 mg/kg. Our results warrant future studies with this probe compound that may establish HePTP as a new drug target for acute leukemic conditions.
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