American Chemical Society
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Inhibition of the Hematopoietic Protein Tyrosine Phosphatase by Phenoxyacetic Acids

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journal contribution
posted on 2011-02-10, 00:00 authored by Ekaterina V. Bobkova, Wallace H. Liu, Sharon Colayco, Justin Rascon, Stefan Vasile, Carlton Gasior, David A. Critton, Xochella Chan, Russell Dahl, Ying Su, Eduard Sergienko, Thomas D. Y. Chung, Tomas Mustelin, Rebecca Page, Lutz Tautz
Protein tyrosine phosphatases 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 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.