2. Academic Validation
  3. Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors

Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors

  • Eur J Med Chem. 2015 Jan 27:90:195-208. doi: 10.1016/j.ejmech.2014.11.023.
Ahmed Z Abdelazem 1,  Mohammad M Al-Sanea 1,  Byung Sun Park 2,  Hye Mi Park 2,  Kyung Ho Yoo 2,  Taebo Sim 2,  Jong Bae Park 3,  Seung-Hoon Lee 3,  So Ha Lee 4
Affiliations

Affiliations

  • 1 Department of Biological Chemistry, Korea University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea; Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea.
  • 2 Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea.
  • 3 Specific Organ Branch, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
  • 4 Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea. Electronic address: LSH6211@kist.re.kr.
PMID: 25461320 DOI: 10.1016/j.ejmech.2014.11.023
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.

Keywords

Non-small cell lung cancer; Pyrazol-4-ylpyrimidine; ROS1 kinase inhibitor; Receptor tyrosine kinase.

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