Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors

Title
Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors
Authors
아흐메드자카리아알사니아박병선박혜미유경호심태보박종배이승훈이소하
Keywords
Pyrazol-4-ylpyrimidine; ROS1 kinase inhibitor; Receptor tyrosine kinase; Non-small cell lung cancer
Issue Date
2015-01
Publisher
European journal of medicinal chemistry
Citation
VOL 90, 195-208
Abstract
With the aim of discovering potent and selective kinase inhibitors targeting ROS1 kinase, we designed, synthesized and screened a series of new pyrazol-4-ylpyrimidine derivatives based on our previously discovered lead compound KIST301072. Compounds 6a–e and 7a–e showed good to excellent activities against ROS1 kinase, and seven out of tested compounds were more potent than KIST301072. Compound 7c was the most potent with IC50 of 24 nM. Moreover, compound 7c showed ROS1 inhibitory selectivity of about 170-fold, relative to that of ALK sharing about 49% amino acid sequence homology with ROS1 kinase in the kinase domain. In silico modeling of 7c at ROS1 active site revealed some essential features for ROS1 inhibitory activity. Based on this study as well as the previous studies, we could build a hypothetical model predicting the required essential features for ROS1 inhibitory activity. The model validity has been tested through a second set of compounds.
URI
http://pubs.kist.re.kr/handle/201004/48792
ISSN
02235234
Appears in Collections:
KIST Publication > Article
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