Small molecule Hedgehog pathway antagonists

Trieu N. Trinh, Eileen A. McLaughlin, Christopher P. Gordon, Ilana R. Bernstein, Victoria J. Pye, Kate A. Redgrove, Adam McCluskey

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


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 Ptch 1 in Shh LIGHT2 cells, with 13 suppressing and 16 stimulating Gli 2 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 IC 50 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.

Original languageEnglish
Pages (from-to)3046-3059
Number of pages14
JournalOrganic and Biomolecular Chemistry
Issue number14
Publication statusPublished - 14 Apr 2017
Externally publishedYes


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