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Citation

BibTex format

@article{Rodgers:2016:10.1021/acschembio.6b00896,
author = {Rodgers, U and Lanyon-Hogg, T and Masumoto, N and Ritzefeld, M and Burke, R and Blagg, J and Magee, A and Tate, E},
doi = {10.1021/acschembio.6b00896},
journal = {ACS Chemical Biology},
pages = {3256--3262},
title = {Characterization of hedgehog acyltransferase inhibitors identifies a small molecule probe for hedgehog signaling by cancer cells},
url = {http://dx.doi.org/10.1021/acschembio.6b00896},
volume = {11},
year = {2016}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Rodgers,U
AU  - Lanyon-Hogg,T
AU  - Masumoto,N
AU  - Ritzefeld,M
AU  - Burke,R
AU  - Blagg,J
AU  - Magee,A
AU  - Tate,E
DO  - 10.1021/acschembio.6b00896
EP  - 3262
PY  - 2016///
SN  - 1554-8937
SP  - 3256
TI  - Characterization of hedgehog acyltransferase inhibitors identifies a small molecule probe for hedgehog signaling by cancer cells
T2  - ACS Chemical Biology
UR  - http://dx.doi.org/10.1021/acschembio.6b00896
UR  - http://hdl.handle.net/10044/1/41906
VL  - 11
ER  -
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Contact

Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ

e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821