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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.issued2016-12-16
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.eissn1554-8937
dc.identifier.doi10.1021/acschembio.6b00896
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.publisherAMER CHEMICAL SOC
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.startdate2016-12
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.volume11
pubs.embargo.termsNo embargo
icr.researchteamMedicinal Chemistry 1
icr.researchteamHit Discovery & Structural Design
dc.contributor.icrauthorBurke, Rosemary


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