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dc.contributor.authorMallinger, Aen_US
dc.contributor.authorCrumpler, Sen_US
dc.contributor.authorPichowicz, Men_US
dc.contributor.authorWaalboer, Den_US
dc.contributor.authorStubbs, Men_US
dc.contributor.authorAdeniji-Popoola, Oen_US
dc.contributor.authorWood, Ben_US
dc.contributor.authorSmith, Een_US
dc.contributor.authorThai, Cen_US
dc.contributor.authorHenley, ATen_US
dc.contributor.authorGeorgi, Ken_US
dc.contributor.authorCourt, Wen_US
dc.contributor.authorHobbs, Sen_US
dc.contributor.authorBox, Gen_US
dc.contributor.authorOrtiz-Ruiz, M-Jen_US
dc.contributor.authorValenti, Men_US
dc.contributor.authorDe Haven Brandon, Aen_US
dc.contributor.authorTePoele, Ren_US
dc.contributor.authorLeuthner, Ben_US
dc.contributor.authorWorkman, Pen_US
dc.contributor.authorAherne, Wen_US
dc.contributor.authorPoeschke, Oen_US
dc.contributor.authorDale, Ten_US
dc.contributor.authorWienke, Den_US
dc.contributor.authorEsdar, Cen_US
dc.contributor.authorRohdich, Fen_US
dc.contributor.authorRaynaud, Fen_US
dc.contributor.authorClarke, PAen_US
dc.contributor.authorEccles, SAen_US
dc.contributor.authorStieber, Fen_US
dc.contributor.authorSchiemann, Ken_US
dc.contributor.authorBlagg, Jen_US
dc.date.accessioned2020-07-28T14:07:04Z
dc.date.issued2015-02-13en_US
dc.identifier.citationJournal of medicinal chemistry, 2015, 58 (4), pp. 1717 - 1735en_US
dc.identifier.issn0022-2623en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3885
dc.identifier.eissn1520-4804en_US
dc.identifier.doi10.1021/jm501436men_US
dc.description.abstractWNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.en_US
dc.formatPrint-Electronicen_US
dc.format.extent1717 - 1735en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectCell Line, Tumoren_US
dc.subjectAnimalsen_US
dc.subjectHumansen_US
dc.subjectMiceen_US
dc.subjectColorectal Neoplasmsen_US
dc.subjectDisease Models, Animalen_US
dc.subjectPyridinesen_US
dc.subjectSpiro Compoundsen_US
dc.subjectLuciferasesen_US
dc.subjectAntineoplastic Agentsen_US
dc.subjectBiological Assayen_US
dc.subjectCrystallography, X-Rayen_US
dc.subjectAdministration, Oralen_US
dc.subjectDrug Evaluation, Preclinicalen_US
dc.subjectXenograft Model Antitumor Assaysen_US
dc.subjectCell Proliferationen_US
dc.subjectMolecular Structureen_US
dc.subjectStructure-Activity Relationshipen_US
dc.subjectBiological Availabilityen_US
dc.subjectDose-Response Relationship, Drugen_US
dc.subjectModels, Molecularen_US
dc.subjectSmall Molecule Librariesen_US
dc.subjectWnt Signaling Pathwayen_US
dc.titleDiscovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen.en_US
dc.typeJournal Article
rioxxterms.versionofrecord10.1021/jm501436men_US
rioxxterms.licenseref.startdate2015-02-13en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfJournal of medicinal chemistryen_US
pubs.issue4en_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/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Tumour Biology & Metastasis
pubs.publication-statusPublisheden_US
pubs.volume58en_US
pubs.embargo.termsNot knownen_US
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamMedicinal Chemistry 1en_US
icr.researchteamSignal Transduction & Molecular Pharmacologyen_US
icr.researchteamTumour Biology & Metastasisen_US
dc.contributor.icrauthorEccles, Suzanneen_US
dc.contributor.icrauthorRaynaud, Florenceen_US
dc.contributor.icrauthorClarke, Paulen_US
dc.contributor.icrauthorWorkman, Paulen_US
dc.contributor.icrauthorBlagg, Julianen_US


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