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dc.contributor.authorRodgers, URen_US
dc.contributor.authorLanyon-Hogg, Ten_US
dc.contributor.authorMasumoto, Nen_US
dc.contributor.authorRitzefeld, Men_US
dc.contributor.authorBurke, Ren_US
dc.contributor.authorBlagg, Jen_US
dc.contributor.authorMagee, AIen_US
dc.contributor.authorTate, EWen_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2017-01-18T15:23:11Z
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/27779865en_US
dc.identifier.citationACS Chem Biol, 11 (12), pp. 3256 - 3262en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/391
dc.identifier.eissn1554-8937en_US
dc.identifier.doi10.1021/acschembio.6b00896en_US
dc.description.abstractThe Sonic Hedgehog (Shh) signaling pathway plays a critical role during embryonic development and cancer progression. N-terminal palmitoylation of Shh by Hedgehog acyltransferase (Hhat) is essential for efficient signaling, raising interest in Hhat as a novel drug target. A recently identified series of dihydrothienopyridines has been proposed to function via this mode of action; however, the lead compound in this series (RUSKI-43) was subsequently shown to possess cytotoxic activity unrelated to canonical Shh signaling. To identify a selective chemical probe for cellular studies, we profiled three RUSKI compounds in orthogonal cell-based assays. We found that RUSKI-43 exhibits off-target cytotoxicity, masking its effect on Hhat-dependent signaling, hence results obtained with this compound in cells should be treated with caution. In contrast, RUSKI-201 showed no off-target cytotoxicity, and quantitative whole-proteome palmitoylation profiling with a bioorthogonal alkyne-palmitate reporter demonstrated specific inhibition of Hhat in cells. RUSKI-201 is the first selective Hhat chemical probe in cells and should be used in future studies of Hhat catalytic function.en_US
dc.format.extent3256 - 3262en_US
dc.languageengen_US
dc.language.isoengen_US
dc.subjectAcyltransferasesen_US
dc.subjectAnimalsen_US
dc.subjectCell Line, Tumoren_US
dc.subjectEnzyme Inhibitorsen_US
dc.subjectHEK293 Cellsen_US
dc.subjectHedgehog Proteinsen_US
dc.subjectHumansen_US
dc.subjectLipoylationen_US
dc.subjectMiceen_US
dc.subjectNIH 3T3 Cellsen_US
dc.subjectNeoplasmsen_US
dc.subjectSignal Transductionen_US
dc.titleCharacterization of Hedgehog Acyltransferase Inhibitors Identifies a Small Molecule Probe for Hedgehog Signaling by Cancer Cells.en_US
dc.typeJournal Article
rioxxterms.versionofrecord10.1021/acschembio.6b00896en_US
rioxxterms.licenseref.startdateen_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfACS Chem Biolen_US
pubs.issue12en_US
pubs.notesNo embargoen_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/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 1 (including Analytical Chemistry and In Silico Chemistry)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design
pubs.publication-statusPublisheden_US
pubs.volume11en_US
pubs.embargo.termsNo embargoen_US
icr.researchteamMedicinal Chemistry 1 (including Analytical Chemistry and In Silico Chemistry)en_US
icr.researchteamHit Discovery & Structural Designen_US
dc.contributor.icrauthorBlagg, Julianen_US
dc.contributor.icrauthorBurke, Rosemaryen_US


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