Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors
DC Field | Value | Language |
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dc.contributor.author | Park, B.S. | - |
dc.contributor.author | Al-Sanea, M.M. | - |
dc.contributor.author | Abdelazem, A.Z. | - |
dc.contributor.author | Park, H.M. | - |
dc.contributor.author | Roh, E.J. | - |
dc.contributor.author | Park, H.-M. | - |
dc.contributor.author | Yoo, K.H. | - |
dc.contributor.author | Sim, T. | - |
dc.contributor.author | Tae, J.S. | - |
dc.contributor.author | Lee, S.H. | - |
dc.date.accessioned | 2021-09-05T16:09:59Z | - |
dc.date.available | 2021-09-05T16:09:59Z | - |
dc.date.created | 2021-06-17 | - |
dc.date.issued | 2014 | - |
dc.identifier.issn | 0968-0896 | - |
dc.identifier.uri | https://scholar.korea.ac.kr/handle/2021.sw.korea/100814 | - |
dc.description.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. © 2014 Elsevier Ltd. All rights reserved. | - |
dc.language | English | - |
dc.language.iso | en | - |
dc.publisher | Elsevier Ltd | - |
dc.subject | 1 [2 chloro 6 [3 (3 methoxy 5 methylphenyl) 1h pyrazol 4 yl]pyrimidin 4 yl]azetidin 3 ol | - |
dc.subject | 1 [6 [3 (3 hydroxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]azetidin 3 ol | - |
dc.subject | 1 [6 [3 (3 methoxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]azetidin 3 ol | - |
dc.subject | 1 [6 [5 (3 hydroxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]azetidin 3 ol | - |
dc.subject | 1 [6 [5 (3 methoxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]azetidin 3 ol | - |
dc.subject | 1 [[6 [3 (3 hydroxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]amino]propan 2 ol | - |
dc.subject | 1 [[6 [3 (3 methoxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]amino] propan 2 ol | - |
dc.subject | 1 [[6 [5 (3 methoxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]amino]propan 1 ol | - |
dc.subject | 2 (2 chloro 6 morpholinopyrimidin 4 yl) 1 (3 methoxy 5 methylphenyl)ethanone | - |
dc.subject | 2 (2,6 dichloropyrimidin 4yl) 1 (3 methoxy 5 methylphenyl)ethanone | - |
dc.subject | 2 [2 chloro 6 (3 hydroxyazetidin 1 yl)pyrimidin 4 yl] 1 (3 methoxy 5 methylphenyl)ethanone | - |
dc.subject | 2 [2 chloro 6 [(2 hydroxypropyl)amino]pyrimidin 4 yl] 1 (3 methoxy 5 methylphenyl)ethanone | - |
dc.subject | 3 methyl 5 [1 methyl 4 [6 morpholino 2 (pyridin 3 yl)pyrimidin 4 yl] 1h pyrazol 3 yl]phenol | - |
dc.subject | 3 methyl 5 [1 methyl 4 [6 morpholino 2 (pyridin 3 yl)pyrimidin 4 yl] 1h pyrazol 5 yl]phenol | - |
dc.subject | 3 [4 [6 [(4 hydroxybutyl)amino] 2 (pyridin 3 yl)pyrimidin 4 yl] 1 methyl 1h pyrazol 3 yl] 5 methylphenol | - |
dc.subject | 4 [2 chloro 6 [3 (3 methoxy 5 methylphenyl) 1h pyrazol 4 yl]pyrimidin 4 yl]morpholine | - |
dc.subject | 4 [6 [3 (3 methoxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]butan 1 ol | - |
dc.subject | 4 [6 [3 (3 methoxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]morpholine | - |
dc.subject | 4 [6 [5 (3 methoxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]morpholine | - |
dc.subject | 4 [[2 chloro 6 [3 (3 methoxy 5 methylphenyl) 1h pyrazol 4 yl]pyrimidin 4 yl]amino]butan 1 ol | - |
dc.subject | 4 [[6 [5 (3 methoxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]amino]butan 1 ol | - |
dc.subject | crizotinib | - |
dc.subject | dasatinib | - |
dc.subject | imatinib | - |
dc.subject | protein c ros | - |
dc.subject | protein tyrosine kinase | - |
dc.subject | protein tyrosine kinase inhibitor | - |
dc.subject | pyrazole derivative | - |
dc.subject | staurosporine | - |
dc.subject | unclassified drug | - |
dc.subject | unindexed drug | - |
dc.subject | adenosine triphosphate | - |
dc.subject | crizotinib | - |
dc.subject | oncoprotein | - |
dc.subject | protein binding | - |
dc.subject | protein kinase inhibitor | - |
dc.subject | pyrazole | - |
dc.subject | pyrazole derivative | - |
dc.subject | pyridine derivative | - |
dc.subject | ROS1 protein, human | - |
dc.subject | article | - |
dc.subject | binding site | - |
dc.subject | biological activity | - |
dc.subject | controlled study | - |
dc.subject | drug design | - |
dc.subject | drug potency | - |
dc.subject | drug protein binding | - |
dc.subject | drug screening | - |
dc.subject | drug selectivity | - |
dc.subject | drug structure | - |
dc.subject | drug synthesis | - |
dc.subject | enzyme assay | - |
dc.subject | human | - |
dc.subject | IC 50 | - |
dc.subject | molecular model | - |
dc.subject | structure activity relation | - |
dc.subject | substitution reaction | - |
dc.subject | antagonists and inhibitors | - |
dc.subject | chemistry | - |
dc.subject | metabolism | - |
dc.subject | molecular docking | - |
dc.subject | protein tertiary structure | - |
dc.subject | synthesis | - |
dc.subject | Adenosine Triphosphate | - |
dc.subject | Binding Sites | - |
dc.subject | Humans | - |
dc.subject | Molecular Docking Simulation | - |
dc.subject | Protein Binding | - |
dc.subject | Protein Kinase Inhibitors | - |
dc.subject | Protein Structure, Te | - |
dc.title | Structure-based optimization and biological evaluation of trisubstituted pyrazole as a core structure of potent ROS1 kinase inhibitors | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Sim, T. | - |
dc.identifier.doi | 10.1016/j.bmc.2014.06.020 | - |
dc.identifier.scopusid | 2-s2.0-84905117717 | - |
dc.identifier.bibliographicCitation | Bioorganic and Medicinal Chemistry, v.22, no.15, pp.3871 - 3878 | - |
dc.relation.isPartOf | Bioorganic and Medicinal Chemistry | - |
dc.citation.title | Bioorganic and Medicinal Chemistry | - |
dc.citation.volume | 22 | - |
dc.citation.number | 15 | - |
dc.citation.startPage | 3871 | - |
dc.citation.endPage | 3878 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.subject.keywordPlus | 1 [2 chloro 6 [3 (3 methoxy 5 methylphenyl) 1h pyrazol 4 yl]pyrimidin 4 yl]azetidin 3 ol | - |
dc.subject.keywordPlus | 1 [6 [3 (3 hydroxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]azetidin 3 ol | - |
dc.subject.keywordPlus | 1 [6 [3 (3 methoxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]azetidin 3 ol | - |
dc.subject.keywordPlus | 1 [6 [5 (3 hydroxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]azetidin 3 ol | - |
dc.subject.keywordPlus | 1 [6 [5 (3 methoxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]azetidin 3 ol | - |
dc.subject.keywordPlus | 1 [[6 [3 (3 hydroxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]amino]propan 2 ol | - |
dc.subject.keywordPlus | 1 [[6 [3 (3 methoxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]amino] propan 2 ol | - |
dc.subject.keywordPlus | 1 [[6 [5 (3 methoxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]amino]propan 1 ol | - |
dc.subject.keywordPlus | 2 (2 chloro 6 morpholinopyrimidin 4 yl) 1 (3 methoxy 5 methylphenyl)ethanone | - |
dc.subject.keywordPlus | 2 (2,6 dichloropyrimidin 4yl) 1 (3 methoxy 5 methylphenyl)ethanone | - |
dc.subject.keywordPlus | 2 [2 chloro 6 (3 hydroxyazetidin 1 yl)pyrimidin 4 yl] 1 (3 methoxy 5 methylphenyl)ethanone | - |
dc.subject.keywordPlus | 2 [2 chloro 6 [(2 hydroxypropyl)amino]pyrimidin 4 yl] 1 (3 methoxy 5 methylphenyl)ethanone | - |
dc.subject.keywordPlus | 3 methyl 5 [1 methyl 4 [6 morpholino 2 (pyridin 3 yl)pyrimidin 4 yl] 1h pyrazol 3 yl]phenol | - |
dc.subject.keywordPlus | 3 methyl 5 [1 methyl 4 [6 morpholino 2 (pyridin 3 yl)pyrimidin 4 yl] 1h pyrazol 5 yl]phenol | - |
dc.subject.keywordPlus | 3 [4 [6 [(4 hydroxybutyl)amino] 2 (pyridin 3 yl)pyrimidin 4 yl] 1 methyl 1h pyrazol 3 yl] 5 methylphenol | - |
dc.subject.keywordPlus | 4 [2 chloro 6 [3 (3 methoxy 5 methylphenyl) 1h pyrazol 4 yl]pyrimidin 4 yl]morpholine | - |
dc.subject.keywordPlus | 4 [6 [3 (3 methoxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]butan 1 ol | - |
dc.subject.keywordPlus | 4 [6 [3 (3 methoxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]morpholine | - |
dc.subject.keywordPlus | 4 [6 [5 (3 methoxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]morpholine | - |
dc.subject.keywordPlus | 4 [[2 chloro 6 [3 (3 methoxy 5 methylphenyl) 1h pyrazol 4 yl]pyrimidin 4 yl]amino]butan 1 ol | - |
dc.subject.keywordPlus | 4 [[6 [5 (3 methoxy 5 methylphenyl) 1 methyl 1h pyrazol 4 yl] 2 (pyridin 3 yl)pyrimidin 4 yl]amino]butan 1 ol | - |
dc.subject.keywordPlus | crizotinib | - |
dc.subject.keywordPlus | dasatinib | - |
dc.subject.keywordPlus | imatinib | - |
dc.subject.keywordPlus | protein c ros | - |
dc.subject.keywordPlus | protein tyrosine kinase | - |
dc.subject.keywordPlus | protein tyrosine kinase inhibitor | - |
dc.subject.keywordPlus | pyrazole derivative | - |
dc.subject.keywordPlus | staurosporine | - |
dc.subject.keywordPlus | unclassified drug | - |
dc.subject.keywordPlus | unindexed drug | - |
dc.subject.keywordPlus | adenosine triphosphate | - |
dc.subject.keywordPlus | crizotinib | - |
dc.subject.keywordPlus | oncoprotein | - |
dc.subject.keywordPlus | protein binding | - |
dc.subject.keywordPlus | protein kinase inhibitor | - |
dc.subject.keywordPlus | pyrazole | - |
dc.subject.keywordPlus | pyrazole derivative | - |
dc.subject.keywordPlus | pyridine derivative | - |
dc.subject.keywordPlus | ROS1 protein, human | - |
dc.subject.keywordPlus | article | - |
dc.subject.keywordPlus | binding site | - |
dc.subject.keywordPlus | biological activity | - |
dc.subject.keywordPlus | controlled study | - |
dc.subject.keywordPlus | drug design | - |
dc.subject.keywordPlus | drug potency | - |
dc.subject.keywordPlus | drug protein binding | - |
dc.subject.keywordPlus | drug screening | - |
dc.subject.keywordPlus | drug selectivity | - |
dc.subject.keywordPlus | drug structure | - |
dc.subject.keywordPlus | drug synthesis | - |
dc.subject.keywordPlus | enzyme assay | - |
dc.subject.keywordPlus | human | - |
dc.subject.keywordPlus | IC 50 | - |
dc.subject.keywordPlus | molecular model | - |
dc.subject.keywordPlus | structure activity relation | - |
dc.subject.keywordPlus | substitution reaction | - |
dc.subject.keywordPlus | antagonists and inhibitors | - |
dc.subject.keywordPlus | chemistry | - |
dc.subject.keywordPlus | metabolism | - |
dc.subject.keywordPlus | molecular docking | - |
dc.subject.keywordPlus | protein tertiary structure | - |
dc.subject.keywordPlus | synthesis | - |
dc.subject.keywordPlus | Adenosine Triphosphate | - |
dc.subject.keywordPlus | Binding Sites | - |
dc.subject.keywordPlus | Humans | - |
dc.subject.keywordPlus | Molecular Docking Simulation | - |
dc.subject.keywordPlus | Protein Binding | - |
dc.subject.keywordPlus | Protein Kinase Inhibitors | - |
dc.subject.keywordPlus | Protein Structure, Te | - |
dc.subject.keywordAuthor | Cancer | - |
dc.subject.keywordAuthor | Kinase inhibitor | - |
dc.subject.keywordAuthor | NSCLC | - |
dc.subject.keywordAuthor | ROS1 | - |
dc.subject.keywordAuthor | Structure-activity relationship | - |
dc.subject.keywordAuthor | Suzuki coupling | - |
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