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

Authors

Xianfeng Gu, University of Rhode Island
Yuehao Wang, University of Rhode Island
Anil Kumar, University of Rhode Island
Guofeng Ye, University of Rhode Island
Keykavous Parang, University of Rhode Island
Gongqin Sun, University of Rhode Island

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.