title: Inhibition of the Hematopoietic Protein Tyrosine Phosphatase by Phenoxyacetic Acids.
abstract: 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.
authors.affiliation: Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Ekaterina V
authors.initials: EV
authors.lastname: Bobkova
authors.forename: Wallace H
authors.initials: WH
authors.lastname: Liu
authors.forename: Sharon
authors.initials: S
authors.lastname: Colayco
authors.forename: Justin
authors.initials: J
authors.lastname: Rascon
authors.forename: Stefan
authors.initials: S
authors.lastname: Vasile
authors.forename: Carlton
authors.initials: C
authors.lastname: Gasior
authors.forename: David A
authors.initials: DA
authors.lastname: Critton
authors.forename: Xochella
authors.initials: X
authors.lastname: Chan
authors.forename: Russell
authors.initials: R
authors.lastname: Dahl
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.forename: Eduard
authors.initials: E
authors.lastname: Sergienko
authors.forename: Thomas D Y
authors.initials: TD
authors.lastname: Chung
authors.forename: Tomas
authors.initials: T
authors.lastname: Mustelin
authors.forename: Rebecca
authors.initials: R
authors.lastname: Page
authors.forename: Lutz
authors.initials: L
authors.lastname: Tautz