Work

Oxime‐Based Click Chemistry in the Development of 3‐Isoxazolecarboxylic Acid Containing Inhibitors of Yersinia pestis Protein Tyrosine Phosphatase, YopH

Year: 2011

Type: article

Abstract: The pathogenicity of Yersinia pestis relies on several effector proteins including YopH, a protein tyrosine phosphatase (PTP). We previously screened a library of analogues based on the ubiquitous PTP substrate para-nitrophenylphosphate (pNPP) and found that incorporation of a 3-phenyl substituent to give 6-nitro-[1,1'-biphenyl]-3-yldihydrogen phosphate (1) enhanced affinity. Herein we report the conversion of 1 from a substrate into an inhibitor by replacing the hydrolysable phosphoryl group with a 3-isoxazolecarboxylic acid moiety and by introduction of an aminooxy group and subsequent diversification using oxime-based click chemistry. This approach led to the identification of non-promiscuous bidentate YopH inhibitors with affinity in the low micromolar range.

Source: ChemMedChem

DOI: 10.1002/cmdc.201100200

Authors: Medhanit Bahta, Terrence R. Burke

Institutions: National Institutes of Health, National Cancer Institute, Center for Cancer Research

Language: English

Topic: Protein Tyrosine Phosphatases

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funders: National Institutes of Health, National Cancer Institute

Awards: G2755035673, G6374948078, Inhibitors of Tyrosine Kinase-Dependent Signaling as Anti-Cancer Agents