Characterization of Hedgehog Acyltransferase Inhibitors Identifies a Small Molecule Probe for Hedgehog Signaling by Cancer Cells.
Date
2016-12-16ICR Author
Author
Rodgers, UR
Lanyon-Hogg, T
Masumoto, N
Ritzefeld, M
Burke, R
Blagg, J
Magee, AI
Tate, EW
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Cell Line, Tumor
NIH 3T3 Cells
Animals
Humans
Mice
Neoplasms
Acyltransferases
Enzyme Inhibitors
Signal Transduction
Hedgehog Proteins
Lipoylation
HEK293 Cells
Research team
Medicinal Chemistry 1
Hit Discovery & Structural Design
Language
eng
License start date
2016-12
Citation
ACS chemical biology, 2016, 11 (12), pp. 3256 - 3262
Publisher
AMER CHEMICAL SOC