title: Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors.
abstract: 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 μM.
authors.affiliation: Department of Chemistry, Yonsei University, 134, Sinchon-dong, Seodaemun-gu, Seoul 120-749, 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, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biological Chemistry, Korea University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-333, 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, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea; Department of Biological Chemistry, Korea University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-333, Republic of Korea.
authors.forename: Ahmed Z
authors.initials: AZ
authors.lastname: Abdelazem
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, 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, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea. Electronic address: r8636@kist.re.kr.
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Roh
authors.affiliation: Advanced Analysis Center, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Hyun-Mee
authors.initials: HM
authors.lastname: Park
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, 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, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea.
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.affiliation: Department of Chemistry, Yonsei University, 134, Sinchon-dong, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors.forename: Jin Sung
authors.initials: JS
authors.lastname: Tae
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea. Electronic address: LSH6211@kist.re.kr.
authors.forename: So Ha
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D000077547:Crizotinib; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; C031280:pyrazole; D000077547:Crizotinib; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human
keywords: Cancer; Kinase inhibitor; NSCLC; ROS1; Structure–activity relationship; Suzuki coupling