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Small molecule Hedgehog pathway antagonists

Journal Article


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.

Publication Date


  • 2017

Citation


  • Trinh, T. N., McLaughlin, E. A., Gordon, C. P., Bernstein, I. R., Pye, V. J., Redgrove, K. A., & McCluskey, A. (2017). Small molecule Hedgehog pathway antagonists. Organic and Biomolecular Chemistry, 15(14), 3046-3059. doi:10.1039/C6OB01959E

Scopus Eid


  • 2-s2.0-85017002203

Start Page


  • 3046

End Page


  • 3059

Volume


  • 15

Issue


  • 14

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.

Publication Date


  • 2017

Citation


  • Trinh, T. N., McLaughlin, E. A., Gordon, C. P., Bernstein, I. R., Pye, V. J., Redgrove, K. A., & McCluskey, A. (2017). Small molecule Hedgehog pathway antagonists. Organic and Biomolecular Chemistry, 15(14), 3046-3059. doi:10.1039/C6OB01959E

Scopus Eid


  • 2-s2.0-85017002203

Start Page


  • 3046

End Page


  • 3059

Volume


  • 15

Issue


  • 14