- Title
- Small molecule hedgehog pathway antagonists
- Creator
- Trinh, Trieu N.; McLaughlin, Eileen A.; Gordon, Christopher P.; Bernstein, Ilana R.; Pye, Victoria J.; Redgrove, Kate A.; McCluskey, Adam
- Relation
- NHMRC
- Relation
- Organic & Biomolecular Chemistry Vol. 15, Issue 14, p. 3046-3059
- Publisher Link
- http://dx.doi.org/10.1039/c6ob01959e
- Publisher
- Royal Society of Chemistry
- Resource Type
- journal article
- Date
- 2017
- Description
- 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.
- Subject
- hedgehog signalling pathway; chemotherapeutic agents; cancer stem cells; cancer
- Identifier
- http://hdl.handle.net/1959.13/1352358
- Identifier
- uon:30867
- Identifier
- ISSN:1477-0520
- Language
- eng
- Reviewed
- Hits: 3046
- Visitors: 1936
- Downloads: 0
| Thumbnail | File | Description | Size | Format |
|---|