Rodgers, U. R., Lanyon-Hogg, T., Masumoto, N., Ritzefeld, M., Burke, R., Blagg, J., Magee, A. I., Tate, E. W. (2016) Characterization of Hedgehog Acyltransferase Inhibitors Identifies a Small Molecule Probe for Hedgehog Signaling by Cancer Cells. ACS CHEMICAL BIOLOGY, 11 (12). pp. 3256-3262. ISSN 1554-8929

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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.

Item Type:	Article
Authors (ICR Faculty only):	Blagg, Julian
All Authors:	Rodgers, U. R., Lanyon-Hogg, T., Masumoto, N., Ritzefeld, M., Burke, R., Blagg, J., Magee, A. I., Tate, E. W.
Additional Information:	ISI Document Delivery No.: EF2TY Times Cited: 0 Cited Reference Count: 47 Rodgers, Ursula R. Lanyon-Hogg, Thomas Masumoto, Naoko Ritzefeld, Markus Burke, Rosemary Blagg, Julian Magee, Anthony I. Tate, Edward W. 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] The authors thank Dr. Suzanne Eaton for the kind gift of the Shh-Light2 cells and Prof. Lawrence Lum for the kind gifts of the Wnt reporter cell line and LGK974 inhibitor. This work was supported by Cancer Research UK (CRUK, C6433/A16402). N.M. held a Ph.D. studentship from the Imperial College London Institute of Chemical Biology, Engineering and Physical Sciences Research Council (EPSRC) Centre for Doctoral Training (EP/F500416/1). M.R. was generously funded by a Marie Curie Intra European Fellowship from the European Commission's Research Executive Agency (FP7-PEOPLE-2013-IEF). J.B. and R.B. are supported by Cancer Research UK (grant number C309/A11566). 0 AMER CHEMICAL SOC WASHINGTON ACS CHEM BIOL
Uncontrolled Keywords:	PANCREATIC DUCTAL ADENOCARCINOMA SONIC-HEDGEHOG CHEMICAL PROBES PROTEIN LIPIDATION TARGET VALIDATION CLICK CHEMISTRY PALMITOYLATION RANGE CHOLESTERYLATION MODULATION
Research teams:	ICR divisions > Cancer Therapeutics > Medicinal Chemistry 1 (including Analytical Chemistry and In Silico Chemistry)
Depositing User:	Barry Jenkins
Date Deposited:	18 Jan 2017 15:19
Last Modified:	18 Jan 2017 15:19
URI:	http://publications.icr.ac.uk/id/eprint/15611

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