期刊
ACS CHEMICAL BIOLOGY
卷 11, 期 12, 页码 3256-3262出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.6b00896
关键词
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资金
- Cancer Research UK (CRUK) [C6433/A16402]
- Imperial College London Institute of Chemical Biology
- Engineering and Physical Sciences Research Council (EPSRC) Centre for Doctoral Training [EP/F500416/1]
- European Commission's Research Executive Agency
- Cancer Research UK [C309/A11566]
- Cancer Research UK [11566, 16402] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/J021199/1] Funding Source: researchfish
- EPSRC [EP/J021199/1] Funding Source: UKRI
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.
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