dc.contributor.author | Rodgers, UR | |
dc.contributor.author | Lanyon-Hogg, T | |
dc.contributor.author | Masumoto, N | |
dc.contributor.author | Ritzefeld, M | |
dc.contributor.author | Burke, R | |
dc.contributor.author | Blagg, J | |
dc.contributor.author | Magee, AI | |
dc.contributor.author | Tate, EW | |
dc.date.accessioned | 2017-01-18T15:23:11Z | |
dc.date.issued | 2016-12-16 | |
dc.identifier.citation | ACS chemical biology, 2016, 11 (12), pp. 3256 - 3262 | |
dc.identifier.issn | 1554-8929 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/391 | |
dc.identifier.eissn | 1554-8937 | |
dc.identifier.doi | 10.1021/acschembio.6b00896 | |
dc.description.abstract | The 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.format | Print-Electronic | |
dc.format.extent | 3256 - 3262 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER CHEMICAL SOC | |
dc.subject | Cell Line, Tumor | |
dc.subject | NIH 3T3 Cells | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Neoplasms | |
dc.subject | Acyltransferases | |
dc.subject | Enzyme Inhibitors | |
dc.subject | Signal Transduction | |
dc.subject | Hedgehog Proteins | |
dc.subject | Lipoylation | |
dc.subject | HEK293 Cells | |
dc.title | Characterization of Hedgehog Acyltransferase Inhibitors Identifies a Small Molecule Probe for Hedgehog Signaling by Cancer Cells. | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.1021/acschembio.6b00896 | |
rioxxterms.licenseref.startdate | 2016-12 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | ACS chemical biology | |
pubs.issue | 12 | |
pubs.notes | No 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-status | Published | |
pubs.volume | 11 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Medicinal Chemistry 1 | |
icr.researchteam | Hit Discovery & Structural Design | |
dc.contributor.icrauthor | Burke, Rosemary | |