title: Design and synthesis of new anticancer pyrimidines with multiple-kinase inhibitory effect.
abstract: A new series of N-substituted-2-aminopyrimidines based on the '4-(pyridin-3-yl)pyrimidin-2-amine' scaffold of Imatinib has been designed and synthesized. A selected group from the target compounds was tested over a panel of 60 cancer cell lines at a single dose concentration of 10microM, and the two most active compounds, 25b and 30, were further tested in a five-dose testing mode to determine their IC(50) values over the 60 cell lines. Compound 30 has showed good potencies and high efficacies, and was accordingly tested at a single dose concentration of 10microM over a panel of 54 kinases. At this concentration, the compound has showed multiple inhibitions over a number of oncogenic kinases, including ABL1, AKT1, LCK, C-SRC, PIM1, FLT3, FYN, and KDR. A molecular modeling study was made by docking of the most active compound 30 and its inactive analog 29 into the kinase domain of ABL1 to investigate their possible binding interactions.
authors.affiliation: Korea Institute of Science and Technology, Cheongryang, Seoul 130-650, Republic of Korea.
authors.forename: Ibrahim Mustafa
authors.initials: IM
authors.lastname: El-Deeb
authors.forename: So Ha
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010879:Piperazines; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl