Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors

Title
Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors
Authors
박병선알사니아아흐메드자카리아박혜미노은주박현미유경호심태보태진성이소하
Keywords
Cancer; Kinase inhibitor; NSCLC; ROS1; Structure-activity relationship; Suzuki coupling
Issue Date
2014-08
Publisher
Bioorganic & medicinal chemistry
Citation
VOL 22, NO 15, 3871-3878
Abstract
Recently inhibition of ROS1 kinase has proven to be a promising strategy for several indications such as glioblastoma, non-small cell lung cancer (NSCLC), and cholangiocarcinoma. Our team reported trisubstituted pyrazole-based ROS1 inhibitors by which two inhibitors showed good IC50 values in enzyme-based screening. To develop more advanced ROS1 inhibitors through SAR this trisubstituted pyrazole-based scaffold has been built. Consequently, 16 compounds have been designed, synthesized and shown potent IC50 values in the enzymatic assay, which are from 13.6 to 283 nM. Molecular modeling studies explain how these ROS1 kinase inhibitors revealed effectively the key interactions with ROS1 ATP binding site. Among these compounds, compound 9a (IC50 = 13.6 nM) has exerted 5 fold potency than crizotinib and exhibited high degree of selectivity (selectivity score value = 0.028) representing the number of non-mutant kinases with biological activity over 90% at 10 μM.
URI
http://pubs.kist.re.kr/handle/201004/48010
ISSN
09680896
Appears in Collections:
KIST Publication > Article
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