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Structure-based design and discovery of novel inhibitors of protein tyrosine phosphatases.

Abstract：

:Protein tyrosine phosphatases (PTPs) are important in the regulation of signal transduction processes. Certain enzymes of this class are considered as potential therapeutic targets in the treatment of a variety of diseases such as diabetes, inflammation, and cancer. However, many PTP inhibitors identified to date are peptide-based and contain a highly charged phosphate-mimicking component. These compounds usually lack membrane permeability and this limits their utility in the inhibition of intracellular phosphatases. In the present study, we have used structure-based design and modeling techniques to explore catalytic-site directed, reversible inhibitors of PTPs. Employing a non-charged phosphate mimic and non-peptidyl structural components, we have successfully designed and synthesized a novel series of trifluoromethyl sulfonyl and trifluoromethyl sulfonamido compounds as PTP inhibitors. This is the first time that an uncharged phosphate mimic is reported in the literature for general, reversible, and substrate-competitive inhibition of PTPs. It is an important discovery because the finding may provide a paradigm for the development of phosphatase inhibitors that enter cells and modify signal transduction.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Huang P,Ramphal J,Wei J,Liang C,Jallal B,McMahon G,Tang C

doi

10.1016/s0968-0896(03)00039-7

subject

Has Abstract

pub_date

2003-04-17 00:00:00

pages

1835-49

issue

8

eissn

0968-0896

issn

1464-3391

pii

S0968089603000397

journal_volume

11

pub_type

杂志文章

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