Abdelazem, Ahmed Z. Al-Sanea, Mohammad M. Park, Byung Sun Park, Hye Mi Yoo, Kyung Ho Sim, Taebo Park, Jong Bae Lee, Seung-Hoon Lee, So Ha 2024-01-20T08:01:05Z 2024-01-20T08:01:05Z 2021-09-05 2015-01-27 0223-5234 https://pubs.kist.re.kr/handle/201004/125849 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 silica 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. (C) 2014 Elsevier Masson SAS. All rights reserved. English ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER CANCER DESIGN Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors Article 10.1016/j.ejmech.2014.11.023 1 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v.90, pp.195 - 208 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 90 195 208 scie scopus 000348951900015 2-s2.0-84911399882 Chemistry, Medicinal Pharmacology & Pharmacy Article CANCER DESIGN Pyrazol-4-ylpyrimidine ROS1 kinase inhibitor Receptor tyrosine kinase Non-small cell lung cancer