Design and evaluation of hydroxamate derivatives as metal-mediated inhibitors of a protein tyrosine kinase
Document Type
Article
Date of Original Version
12-14-2006
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. © 2006 American Chemical Society.
Publication Title, e.g., Journal
Journal of Medicinal Chemistry
Volume
49
Issue
25
Citation/Publisher Attribution
Gu, Xianfeng, Yuehao Wang, Anil Kumar, Guofeng Ye, Keykavous Parang, and Gongqin Sun. "Design and evaluation of hydroxamate derivatives as metal-mediated inhibitors of a protein tyrosine kinase." Journal of Medicinal Chemistry 49, 25 (2006). doi: 10.1021/jm061058c.