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The hematopoietic protein tyrosine phosphatase (HePTP) is implicated in the development of acute leukemias, including T cell acute lymphoblastic leukemia (T-ALL) and acute myelogenous leukemia (AML), through its ability to negatively regulate the MAP kinases ERK1/2 and p38. Although transient activation of MAP kinases is crucial for growth and proliferation, prolonged activation of these important signaling molecules induces differentiation, cell cycle arrest, and apoptosis. Specific HePTP inhibitors may promote the latter and thereby may halt the growth of cancer cells. 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 …