Development of Molecular Probes for Second-Site Screening and Design of Protein Tyrosine Phosphatase Inhibitors

• Published in: Journal of medicinal chemistry 2007-05, Vol.50 (9), p.2137-2143
• Main Authors: Vazquez, Jesus, Tautz, Lutz, Ryan, Jennifer J, Vuori, Kristiina, Mustelin, Tomas, Pellecchia, Maurizio
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Bacterial Outer Membrane Proteins - antagonists & inhibitors; Bacterial Outer Membrane Proteins - chemistry; Biological and medical sciences; Catalytic Domain; Cyclic N-Oxides - chemical synthesis; Cyclic N-Oxides - chemistry; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Furans - chemical synthesis; Furans - chemistry; Hydrolases; Magnetic Resonance Spectroscopy; Medical sciences; Miscellaneous; Models, Molecular; Pharmacology. Drug treatments; Protein Tyrosine Phosphatases - antagonists & inhibitors; Protein Tyrosine Phosphatases - chemistry; Salicylates - chemical synthesis; Salicylates - chemistry; Spin Labels - chemical synthesis; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061481l

We report on the design, synthesis, and evaluation of a series of furanyl-salicyl-nitroxide derivatives as effective chemical probes for second-site screening against phosphotyrosine phosphatases (PTPs) using NMR-based techniques. The compounds have been tested against a panel of PTPs to assess their ability to inhibit a broad spectrum of these phosphatases. The utility of the derived compounds is illustrated with the phosphatase YopH, a bacterial toxin from Yersinia pestis. Novel chemical fragments were identified during an NMR-based screen for compounds that are capable of binding on the surface of YopH in regions adjacent the catalytic site in the presence of the spin-labeled compounds. Our data demonstrate the value of the derived chemical probes for NMR-based second-site screening in PTPs.