title: Design, synthesis, screening, and molecular modeling study of a new series of ROS1 receptor tyrosine kinase inhibitors.
abstract: A series of rationally designed ROS1 tyrosine kinase inhibitors was synthesized and screened. Compound 12b has showed good potency with IC50 value of 209 nM, which is comparable with that of the reference lead compound 1. Molecular modeling studies have been performed, that is, a homology model for ROS1 was built, and the screened inhibitors were docked into its major identified binding site. The docked poses along with the activity data have revealed a group of the essential features for activity. Overall, simplification of the lead compound 1 into compound 12b has maintained the activity, while facilitated the synthetic advantages. A molecular interaction model for ROS1 kinase and inhibitors has been proposed.
authors.affiliation: Department of Biomolecular Science, University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea.
authors.forename: Ibrahim M
authors.initials: IM
authors.lastname: El-Deeb
authors.forename: Byung Sun
authors.initials: BS
authors.lastname: Park
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Jung
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Yoo
authors.forename: Chang-Hyun
authors.initials: CH
authors.lastname: Oh
authors.forename: Seung Joo
authors.initials: SJ
authors.lastname: Cho
authors.forename: Dong Keun
authors.initials: DK
authors.lastname: Han
authors.forename: Jae Yeol
authors.initials: JY
authors.lastname: Lee
authors.forename: So Ha
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D003408:Cresols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D003408:Cresols; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human