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.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Abdelazem AZ,Al-Sanea MM,Park BS,Park HM,Yoo KH,Sim T,Park JB,Lee SH,Lee SHdoi
10.1016/j.ejmech.2014.11.023subject
Has Abstractpub_date
2015-01-27 00:00:00pages
195-208eissn
0223-5234issn
1768-3254pii
S0223-5234(14)01045-9journal_volume
90pub_type
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