title: ATP-phosphopeptide conjugates as inhibitors of Src tyrosine kinases.
abstract: A number of Src SH2 domain inhibitors enhance the kinase catalytic activity by switching the closed inactive to the open active conformation. ATP-phosphopeptide conjugates were designed and synthesized as Src tyrosine kinase inhibitors based on a tetrapeptide sequence pTyr-Glu-Glu-Ile (pYEEI) and ATP to block the SH2 domain signaling and substrate phosphorylation by ATP, respectively. In general, ATP-phosphopeptide conjugates with optimal linkers such as compounds 5 and 7 (K(i) = 1.7-2.6 microM) showed higher binding affinities to the ATP-binding site relative to the other ATP-phosphopeptide conjugates having short or long linkers, 1-4 and 6, (K(i) = 10.1-16.1 microM) and ATP (K(m) = 74 microM). These ATP-phosphopeptide conjugates may serve as novel templates for designing protein tyrosine kinase inhibitors to block SH2 mediated protein-protein interactions and to counter the activation of enzyme that resulted from the SH2 inhibition.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, 41 Lower College Road, Kingston, Rhode Island 02881, USA.
authors.forename: Nguyen-Hai
authors.initials: NH
authors.lastname: Nam
authors.forename: Sungsoo
authors.initials: S
authors.lastname: Lee
authors.forename: Guofeng
authors.initials: G
authors.lastname: Ye
authors.forename: Gongqin
authors.initials: G
authors.lastname: Sun
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D010748:Phosphopeptides / Q000737:chemistry* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D010748:Phosphopeptides; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D019061:src-Family Kinases