title: Oxime-based click chemistry in the development of 3-isoxazolecarboxylic acid containing inhibitors of Yersinia pestis protein tyrosine phosphatase, YopH.
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.
authors.affiliation: Chemical Biology Laboratory, Molecular Discovery Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, P.O. Box, Bldg. 376, Boyles St., Frederick, MD 21702, USA.
authors.forename: Medhanit
authors.initials: M
authors.lastname: Bahta
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D057930:Click Chemistry; D003198:Computer Simulation; D007555:Isoxazoles / Q000737:chemistry*; D007700:Kinetics; D010091:Oximes / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D015010:Yersinia pestis / Q000201:enzymology*
chemical_list: D001425:Bacterial Outer Membrane Proteins; D002264:Carboxylic Acids; D007555:Isoxazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D017027:Protein Tyrosine Phosphatases; C067571:yopH protein, Yersinia