Characterization of hedgehog acyltransferase inhibitors identifies a small molecule probe for hedgehog signaling by cancer cells

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Title: Characterization of hedgehog acyltransferase inhibitors identifies a small molecule probe for hedgehog signaling by cancer cells
Authors: Rodgers, U
Lanyon-Hogg, T
Masumoto, N
Ritzefeld, M
Burke, R
Blagg, J
Magee, A
Tate, E
Item Type: Journal Article
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.
Issue Date: 25-Oct-2016
Date of Acceptance: 13-Oct-2016
URI: http://hdl.handle.net/10044/1/41906
DOI: https://dx.doi.org/10.1021/acschembio.6b00896
ISSN: 1554-8937
Publisher: American Chemical Society
Start Page: 3256
End Page: 3262
Journal / Book Title: ACS Chemical Biology
Volume: 11
Issue: 12
Copyright Statement: © 2016 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Sponsor/Funder: Cancer Research UK
Commission of the European Communities
Funder's Grant Number: C6433/A16402
PIEF-GA-2013-623648
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
PANCREATIC DUCTAL ADENOCARCINOMA
SONIC-HEDGEHOG
CHEMICAL PROBES
PROTEIN LIPIDATION
TARGET VALIDATION
CLICK CHEMISTRY
PALMITOYLATION
RANGE
CHOLESTERYLATION
MODULATION
Acyltransferases
Animals
Cell Line, Tumor
Enzyme Inhibitors
HEK293 Cells
Hedgehog Proteins
Humans
Lipoylation
Mice
NIH 3T3 Cells
Neoplasms
Signal Transduction
Organic Chemistry
03 Chemical Sciences
06 Biological Sciences
Publication Status: Published
Appears in Collections:Chemistry
Biological and Biophysical Chemistry
National Heart and Lung Institute
Faculty of Medicine
Faculty of Natural Sciences



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