Design and evaluation of hydroxamate derivatives as metal-mediated inhibitors of a protein tyrosine kinase

Xianfeng Gu, Yuehao Wang, Anil Kumar, Guofeng Ye, Keykavous Parang, Gongqin Sun

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)7532-7539
Number of pages8
JournalJournal of Medicinal Chemistry
Volume49
Issue number25
DOIs
StatePublished - Dec 14 2006
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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