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dc.contributor.authorRodgers, UR
dc.contributor.authorLanyon-Hogg, T
dc.contributor.authorMasumoto, N
dc.contributor.authorRitzefeld, M
dc.contributor.authorBurke, R
dc.contributor.authorBlagg, J
dc.contributor.authorMagee, AI
dc.contributor.authorTate, EW
dc.date.accessioned2017-01-18T15:23:11Z
dc.date.issued2016-12
dc.identifier.citationACS chemical biology, 2016, 11 (12), pp. 3256 - 3262
dc.identifier.issn1554-8929
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.
dc.formatPrint-Electronic
dc.format.extent3256 - 3262
dc.languageeng
dc.language.isoeng
dc.subjectCell Line, Tumor
dc.subjectNIH 3T3 Cells
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectNeoplasms
dc.subjectAcyltransferases
dc.subjectEnzyme Inhibitors
dc.subjectSignal Transduction
dc.subjectHedgehog Proteins
dc.subjectLipoylation
dc.subjectHEK293 Cells
dc.titleCharacterization of Hedgehog Acyltransferase Inhibitors Identifies a Small Molecule Probe for Hedgehog Signaling by Cancer Cells.
dc.typeJournal Article
rioxxterms.versionofrecord10.1021/acschembio.6b00896
rioxxterms.licenseref.startdate2016-12en_US
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfACS chemical biology
pubs.issue12
pubs.notesNo embargo
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
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.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
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-statusPublished
pubs.volume11en_US
pubs.embargo.termsNo embargo
icr.researchteamMedicinal Chemistry 1en_US
icr.researchteamHit Discovery & Structural Designen_US
dc.contributor.icrauthorBlagg, Julianen
dc.contributor.icrauthorBurke, Rosemaryen


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