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 journalArticle

1 Citation (Scopus)

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 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
Volume15
Issue number14
DOIs
Publication statusPublished - 14 Apr 2017
Externally publishedYes

Fingerprint

Amides
Tryptophan
inhibitors
Libraries
Amines
indoles
Messenger RNA
Molecules
tryptophan
Quinolones
carboxylic acids
amides
molecules
amines
Scaffolds
indole-2-carboxylic acid
synthesis
cells
indole

Cite this

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. https://doi.org/10.1039/C6OB01959E
Trinh, Trieu N. ; McLaughlin, Eileen A. ; Gordon, Christopher P. ; Bernstein, Ilana R. ; Pye, Victoria J. ; Redgrove, Kate A. ; McCluskey, Adam. / Small molecule Hedgehog pathway antagonists. In: Organic and Biomolecular Chemistry. 2017 ; Vol. 15, No. 14. pp. 3046-3059.
@article{12b7f5538c214c33bfd666ed45bb8b89,
title = "Small molecule Hedgehog pathway antagonists",
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 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.",
keywords = "Hedgehogs, Hedgehog Proteins, hedgehog pathway, small molecule libraries",
author = "Trinh, {Trieu N.} and McLaughlin, {Eileen A.} and Gordon, {Christopher P.} and Bernstein, {Ilana R.} and Pye, {Victoria J.} and Redgrove, {Kate A.} and Adam McCluskey",
year = "2017",
month = "4",
day = "14",
doi = "10.1039/C6OB01959E",
language = "English",
volume = "15",
pages = "3046--3059",
journal = "Organic Molecular Chemistry",
issn = "1477-0520",
publisher = "Royal Society of Chemistry",
number = "14",

}

Trinh, TN, McLaughlin, EA, Gordon, CP, Bernstein, IR, Pye, VJ, Redgrove, KA & McCluskey, A 2017, 'Small molecule Hedgehog pathway antagonists', Organic and Biomolecular Chemistry, vol. 15, no. 14, pp. 3046-3059. https://doi.org/10.1039/C6OB01959E

Small molecule Hedgehog pathway antagonists. / Trinh, Trieu N.; McLaughlin, Eileen A.; Gordon, Christopher P.; Bernstein, Ilana R.; Pye, Victoria J.; Redgrove, Kate A.; McCluskey, Adam.

In: Organic and Biomolecular Chemistry, Vol. 15, No. 14, 14.04.2017, p. 3046-3059.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Small molecule Hedgehog pathway antagonists

AU - Trinh, Trieu N.

AU - McLaughlin, Eileen A.

AU - Gordon, Christopher P.

AU - Bernstein, Ilana R.

AU - Pye, Victoria J.

AU - Redgrove, Kate A.

AU - McCluskey, Adam

PY - 2017/4/14

Y1 - 2017/4/14

N2 - 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.

AB - 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.

KW - Hedgehogs

KW - Hedgehog Proteins

KW - hedgehog pathway

KW - small molecule libraries

UR - http://www.scopus.com/inward/record.url?scp=85017002203&partnerID=8YFLogxK

UR - http://www.mendeley.com/research/small-molecule-hedgehog-pathway-antagonists

U2 - 10.1039/C6OB01959E

DO - 10.1039/C6OB01959E

M3 - Article

VL - 15

SP - 3046

EP - 3059

JO - Organic Molecular Chemistry

JF - Organic Molecular Chemistry

SN - 1477-0520

IS - 14

ER -

Trinh TN, McLaughlin EA, Gordon CP, Bernstein IR, Pye VJ, Redgrove KA et al. Small molecule Hedgehog pathway antagonists. Organic and Biomolecular Chemistry. 2017 Apr 14;15(14):3046-3059. https://doi.org/10.1039/C6OB01959E