Journal
CHEMMEDCHEM
Volume 6, Issue 8, Pages 1363-1370Publisher
WILEY-BLACKWELL
DOI: 10.1002/cmdc.201100200
Keywords
aminooxy platform; docking studies; inhibitors; oxime-based click chemistry; substrate screening
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Funding
- National Institutes of Health (NIH), Center for Cancer Research, NCI-Frederick
- National Cancer Institute, NIH
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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.
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