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J Med Chem. 2011 Apr 28;54(8):2933-43. doi: 10.1021/jm200022g. Epub 2011 Mar 28.

Utilization of nitrophenylphosphates and oxime-based ligation for the development of nanomolar affinity inhibitors of the Yersinia pestis outer protein H (YopH) phosphatase.

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Chemical Biology Laboratory, Molecular Discovery Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, NCI-Frederick, Frederick, Maryland 21702, United States.


Our current study reports the first K(M) optimization of a library of nitrophenylphosphate-containing substrates for generating an inhibitor lead against the Yersinia pestis outer protein phosphatase (YopH). A high activity substrate identified by this method (K(M) = 80 μM) was converted from a substrate into an inhibitor by replacement of its phosphate group with difluoromethylphosphonic acid and by attachment of an aminooxy handle for further structural optimization by oxime ligation. A cocrystal structure of this aminooxy-containing platform in complex with YopH allowed the identification of a conserved water molecule proximal to the aminooxy group that was subsequently employed for the design of furanyl-based oxime derivatives. By this process, a potent (IC(50) = 190 nM) and nonpromiscuous inhibitor was developed with good YopH selectivity relative to a panel of phosphatases. The inhibitor showed significant inhibition of intracellular Y. pestis replication at a noncytotoxic concentration. The current work presents general approaches to PTP inhibitor development that may be useful beyond YopH.

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