Design, synthesis and biological evaluation of new potent and highly selective ROS1-tyrosine kinase inhibitor

• Published in: Bioorganic & medicinal chemistry letters 2009-08, Vol.19 (16), p.4720-4723
• Main Authors: Park, Byung Sun, El-Deeb, Ibrahim M., Yoo, Kyung Ho, Oh, Chang-Hyun, Cho, Seung Joo, Han, Dong Keun, Lee, Hye-Seung, Lee, Jae Yeol, Lee, So Ha
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Astrocytoma; Astrocytoma - drug therapy; Biological and medical sciences; Cancer; Drug Design; General aspects; Glioblastoma multiforme; Humans; Kinase inhibitor; Medical sciences; Pharmacology. Drug treatments; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Pyrazole; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; ROS1; Selectivity; Tyrosine kinase
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.06.066

ROS1 protein is a receptor tyrosine kinase that has been reported mainly in meningiomas and astrocytomas, and until now, there is no selective inhibitor for this kinase. In this study, we illustrate for the synthesis of a highly potent selective inhibitor for ROS1 kinase. The synthesized compound 1 was tested initially at a single dose concentration of 10 μM over 45 different kinases. At this concentration, a 94% inhibition of the enzymatic activity of ROS1 kinase was observed, while the inhibition in activity was below 30% in all of the other kinases. The pyrazole compound 1 showed an IC 50 value of 199 nM for ROS1 kinase. ROS1 protein is a receptor tyrosine kinase that has been reported mainly in meningiomas and astrocytomas, and until now, there is no selective inhibitor for this kinase. In this study, we illustrate for the synthesis of a highly potent and selective inhibitor for ROS1 kinase. The synthesized compound 1 was tested initially at a single dose concentration of 10 μM over 45 different kinases. At this concentration, a 94% inhibition of the enzymatic activity of ROS1 kinase was observed, while the inhibition in activity was below 30% in all of the other kinases. The pyrazole compound 1 was further tested in a 10-dose IC 50 mode and showed an IC 50 value of 199 nM for ROS1 kinase. The compound 1 can be used as a promising lead for the development of new selective inhibitors for ROS1 kinase, and it may open the way for new selective therapeutics for astrocytomas.