Park, Byung Sun Al-Sanea, Mohammad M. Abdelazem, Ahmed Z. Park, Hye Mi Roh, Eun Joo Park, Hyun-Mee Yoo, Kyung Ho Sim, Taebo Tae, Jin Sung Lee, So Ha 2024-01-20T09:04:02Z 2024-01-20T09:04:02Z 2021-09-05 2014-08-01 0968-0896 https://pubs.kist.re.kr/handle/201004/126495 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 mu M. (C) 2014 Elsevier Ltd. All rights reserved. English PERGAMON-ELSEVIER SCIENCE LTD ANAPLASTIC LYMPHOMA KINASE CELL LUNG-CANCER TARGETING ROS1 GENE DERIVATIVES CRIZOTINIB DESIGN Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors Article 10.1016/j.bmc.2014.06.020 1 BIOORGANIC & MEDICINAL CHEMISTRY, v.22, no.15, pp.3871 - 3878 BIOORGANIC & MEDICINAL CHEMISTRY 22 15 3871 3878 scie scopus 000339859700009 2-s2.0-84905117717 Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic Biochemistry & Molecular Biology Pharmacology & Pharmacy Chemistry Article ANAPLASTIC LYMPHOMA KINASE CELL LUNG-CANCER TARGETING ROS1 GENE DERIVATIVES CRIZOTINIB DESIGN Cancer Kinase inhibitor NSCLC ROS1 Structure-activity relationship Suzuki coupling