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Issue 14, 2017
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Small molecule Hedgehog pathway antagonists

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Abstract

Leveraging our quinolone-1-(2H)-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-(1H-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-(1H-indol-3-yl)-ethyl]-amine scaffold afforded two sub-micro molar potent inhibitors of Gli expression with 5-methoxy-1H-indole-2-carboxylic acid benzo[1,3]dioxol-5-ylmethyl-[2-(1H-indol-3-yl)-ethyl]-amide 29 and 5-chloro-1H-indole-2-carboxylic acid benzo[1,3]dioxol-5-ylmethyl-[2-(1H-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.

Graphical abstract: Small molecule Hedgehog pathway antagonists

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Publication details

The article was received on 05 Sep 2016, accepted on 03 Mar 2017 and first published on 03 Mar 2017


Article type: Paper
DOI: 10.1039/C6OB01959E
Citation: Org. Biomol. Chem., 2017,15, 3046-3059
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    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, 3046
    DOI: 10.1039/C6OB01959E

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