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Title: | Design and Evaluation of Hydroxamate Derivatives as Metal-Mediated Inhibitors of a Protein Tyrosine Kinase |
Authors: | Kumar, Anil |
Keywords: | Chemistry Peptides and proteins Monomers Phenyls |
Issue Date: | 2006 |
Publisher: | ACS |
Abstract: | Protein tyrosine kinases use two Mg2+ ions as cofactors in catalysis, one as the ATP−Mg complex (M1) and the other as an essential activator (M2). The M2-binding site has high affinity for transition metal cations such as cobalt and zinc. Taking advantage of this high affinity, we examined hydroxamates as metal-mediated inhibitors against C-terminal Src kinase (Csk), a protein tyrosine kinase. Of a small group of amino acid hydroxamates, tyrosine and phenylalanine hydroxamates inhibited Csk activity only in the presence of Co2+. Four classes of phenylalanine and tyrosine hydroxamate derivatives were synthesized and evaluated as metal-mediated inhibitors of Csk, leading to improved inhibition and a better understanding of the structure−activity relationships. This study suggests that hydroxamates may serve as a general scaffold for developing metal-mediated inhibitors against protein tyrosine kinases. To the best of our knowledge, this is the first report of designing metal-mediated inhibitors against a protein tyrosine kinase by targeting a metal binding site. |
URI: | https://pubs.acs.org/doi/full/10.1021/jm061058c http://dspace.bits-pilani.ac.in:8080/xmlui/handle/123456789/2954 |
Appears in Collections: | Department of Chemistry |
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