title: Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ROS1 kinase inhibitors.
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.
authors.affiliation: 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.
authors.forename: Ahmed Z
authors.initials: AZ
authors.lastname: Abdelazem
authors.affiliation: 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.
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Al-Sanea
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea.
authors.forename: Byung Sun
authors.initials: BS
authors.lastname: Park
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea.
authors.forename: Hye Mi
authors.initials: HM
authors.lastname: Park
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea.
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Yoo
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea.
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.affiliation: Specific Organ Branch, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Jong Bae
authors.initials: JB
authors.lastname: Park
authors.affiliation: Specific Organ Branch, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea. Electronic address: LSH6211@kist.re.kr.
authors.forename: So Ha
authors.initials: SH
authors.lastname: Lee
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C000601740:pyrazol-4-ylpyrimidine; D020794:Receptor Protein-Tyrosine Kinases
keywords: Non-small cell lung cancer; Pyrazol-4-ylpyrimidine; ROS1 kinase inhibitor; Receptor tyrosine kinase