Small molecule Hedgehog pathway antagonists (original) (raw)
* Corresponding authors
a Chemistry, Priority Research Centre for Chemical Biology, University of Newcastle, University Drive Callaghan, NSW 2308, Australia
E-mail: Adam.McCluskey@newcastle.edu.au
Fax: +61(2)49215472
Tel: +61(2)49 216486
b Biology, Priority Research Centre for Chemical Biology, University of Newcastle, University Drive Callaghan, NSW 2308, Australia
c Nanoscale Organization and Dynamics Group, School of Science and Health, University of Western Sydney, Penrith South Dc, NSW, Australia
Abstract
Leveraging our quinolone-1-(2_H_)-one based Hedgehog signalling pathway (HSP) inhibitors we have developed two new classes of HSP inhibitors based on: L-tryptophan and benzo[1,3]dioxol-5-ylmethyl-[2-(1_H_-indol-3-yl)-ethyl]-amine. Synthesis of focused compound libraries identified six L-tryptophan based inhibitors, and two stimulators, of Gli at 10 μM compound concentration. 2,4-Dichloro-13 and indole 16 suppressed mRNA expression of Ptch1 in Shh LIGHT2 cells, with 13 suppressing and 16 stimulating Gli2 mRNA expression. Focused library development of the benzo[1,3]dioxol-5-ylmethyl-[2-(1_H_-indol-3-yl)-ethyl]-amine scaffold afforded two sub-micro molar potent inhibitors of Gli expression with 5-methoxy-1_H_-indole-2-carboxylic acid benzo[1,3]dioxol-5-ylmethyl-[2-(1_H_-indol-3-yl)-ethyl]-amide 29 and 5-chloro-1_H_-indole-2-carboxylic acid benzo[1,3]dioxol-5-ylmethyl-[2-(1_H_-indol-3-yl)-ethyl]-amide 30 returning IC50 values of 0.5 and 0.24 μM, respectively. Neither 29 nor 30 acted directly on Smo with our data supporting inhibition of the HSP downstream of Smo.
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Article information
DOI
https://doi.org/10.1039/C6OB01959E
Article type
Paper
Submitted
05 Sep 2016
Accepted
03 Mar 2017
First published
03 Mar 2017
Download Citation
Org. Biomol. Chem., 2017,15, 3046-3059
Permissions
Small molecule Hedgehog pathway antagonists
T. N. Trinh, E. A. McLaughlin, C. P. Gordon, I. R. Bernstein, V. J. Pye, K. A. Redgrove and A. McCluskey,Org. Biomol. Chem., 2017, 15, 3046DOI: 10.1039/C6OB01959E
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