Small molecule Hedgehog pathway antagonists.
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 Ptch1in Shh LIGHT2 cells, with 13 suppressing and 16 stimulating Gli2mRNA 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 IC50values 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.
Chemistry, Priority Research Centre for Chemical Biology, University of Newcastle, University Drive Callaghan, NSW 2308, Australia. Adam.McCluskey@newcastle.edu.au.
Trieu N
TN
Trinh
Biology, Priority Research Centre for Chemical Biology, University of Newcastle, University Drive Callaghan, NSW 2308, Australia.
Eileen A
http://orcid.org/0000-0002-5837-3876
EA
McLaughlin
Chemistry, Priority Research Centre for Chemical Biology, University of Newcastle, University Drive Callaghan, NSW 2308, Australia. Adam.McCluskey@newcastle.edu.au and Nanoscale Organization and Dynamics Group, School of Science and Health, University of Western Sydney, Penrith South Dc, NSW, Australia.
Christopher P
http://orcid.org/0000-0001-7583-5609
CP
Gordon
Biology, Priority Research Centre for Chemical Biology, University of Newcastle, University Drive Callaghan, NSW 2308, Australia.
Ilana R
IR
Bernstein
Biology, Priority Research Centre for Chemical Biology, University of Newcastle, University Drive Callaghan, NSW 2308, Australia.
Victoria J
VJ
Pye
Biology, Priority Research Centre for Chemical Biology, University of Newcastle, University Drive Callaghan, NSW 2308, Australia.
Kate A
KA
Redgrove
Chemistry, Priority Research Centre for Chemical Biology, University of Newcastle, University Drive Callaghan, NSW 2308, Australia. Adam.McCluskey@newcastle.edu.au.
Adam
http://orcid.org/0000-0001-7125-863X
A
McCluskey
D002460:Cell Line; D053823:Hedgehog Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000494:pharmacology*
D053823:Hedgehog Proteins; D054852:Small Molecule Libraries