Design and evaluation of hydroxamate derivatives as metal-mediated inhibitors of a protein tyrosine kinase.
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.
Gu
Xianfeng
X
Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island 02881, USA.
Wang
Yuehao
Y
Kumar
Anil
A
Ye
Guofeng
G
Parang
Keykavous
K
Sun
Gongqin
G
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*
D002413:Cations, Divalent; D006877:Hydroxamic Acids; D003035:Cobalt; D014443:Tyrosine; D010649:Phenylalanine; D019061:src-Family Kinases