title: Design and evaluation of hydroxamate derivatives as metal-mediated inhibitors of a protein tyrosine kinase.
abstract: Protein tyrosine kinases use two Mg(2+) 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 Co(2+). 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.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island 02881, USA.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Gu
authors.forename: Yuehao
authors.initials: Y
authors.lastname: Wang
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.forename: Guofeng
authors.initials: G
authors.lastname: Ye
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
authors.forename: Gongqin
authors.initials: G
authors.lastname: Sun
mesh_terms: D002413:Cations, Divalent; D003035:Cobalt / Q000737:chemistry*; D015195:Drug Design; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D002413:Cations, Divalent; D006877:Hydroxamic Acids; D003035:Cobalt; D014443:Tyrosine; D010649:Phenylalanine; D019061:src-Family Kinases