Design, synthesis, screening, and molecular modeling study of a new series of ROS1 receptor tyrosine kinase inhibitors.
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.
El-Deeb
Ibrahim M
IM
Department of Biomolecular Science, University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea.
Park
Byung Sun
BS
Jung
Su Jin
SJ
Yoo
Kyung Ho
KH
Oh
Chang-Hyun
CH
Cho
Seung Joo
SJ
Han
Dong Keun
DK
Lee
Jae Yeol
JY
Lee
So Ha
SH
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
D000970:Antineoplastic Agents; D003408:Cresols; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human