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dc.contributor.authorWatts, Een_US
dc.contributor.authorHeidenreich, Den_US
dc.contributor.authorTucker, Een_US
dc.contributor.authorRaab, Men_US
dc.contributor.authorStrebhardt, Ken_US
dc.contributor.authorChesler, Len_US
dc.contributor.authorKnapp, Sen_US
dc.contributor.authorBellenie, Ben_US
dc.contributor.authorHoelder, Sen_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2019-03-08T11:49:54Z
dc.date.issued2019-03-14en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/30789735en_US
dc.identifier.citationJ Med Chem, 2019, 62 (5), pp. 2618 - 2637en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3145
dc.identifier.eissn1520-4804en_US
dc.identifier.doi10.1021/acs.jmedchem.8b01947en_US
dc.description.abstractConcomitant inhibition of anaplastic lymphoma kinase (ALK) and bromodomain-4 (BRD4) is a potential therapeutic strategy for targeting two key oncogenic drivers that co-segregate in a significant fraction of high-risk neuroblastoma patients, mutation of ALK and amplification of MYCN. Starting from known dual polo-like kinase (PLK)-1-BRD4 inhibitor BI-2536, we employed structure-based design to redesign this series toward compounds with a dual ALK-BRD4 profile. These efforts led to compound ( R)-2-((2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-7-ethyl-5-methyl-8-((4-methylthiophen-2-yl)methyl)-7,8-dihydropteridin-6(5 H)-one (16k) demonstrating improved ALK activity and significantly reduced PLK-1 activity, while maintaining BRD4 activity and overall kinome selectivity. We demonstrate the compounds' on-target engagement with ALK and BRD4 in cells as well as favorable broad kinase and bromodomain selectivity.en_US
dc.format.extent2618 - 2637en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleDesigning Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-02-21en_US
rioxxterms.versionofrecord10.1021/acs.jmedchem.8b01947en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2019-03-14en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfJ Med Chemen_US
pubs.issue5en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 4
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics
pubs.publication-statusPublisheden_US
pubs.volume62en_US
pubs.embargo.termsNot knownen_US
icr.researchteamMedicinal Chemistry 4en_US
icr.researchteamPaediatric Solid Tumour Biology and Therapeuticsen_US
dc.contributor.icrauthorWatts, Ellenen_US
dc.contributor.icrauthorHoelder, Swenen_US
dc.contributor.icrauthorChesler, Louisen_US


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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/