A useful approach to identify novel small-molecule inhibitors of Wnt-dependent transcription.
The Wnt signaling pathway is frequently deregulated in cancer due to mutations in genes encoding APC, beta-catenin, and axin. To identify small-molecule inhibitors of Wnt signaling as potential therapeutics, a diverse chemical library was screened using a transcription factor reporter cell line in which the activity of the pathway was induced at the level of Disheveled protein. A series of deconvolution studies was used to focus on three compound series that selectively killed cancer cell lines with constitutive Wnt signaling. Activities of the compounds included the ability to induce degradation of beta-catenin that had been stabilized by a glycogen synthase kinase-3 (GSK-3) inhibitor. This screen illustrates a practical approach to identify small-molecule inhibitors of Wnt signaling that can seed the development of agents suitable to treat patients with Wnt-dependent tumors.
Ewan
Kenneth
K
School of Bioscience, Cardiff University, Cardiff, United Kingdom.
Pajak
Bozena
B
Stubbs
Mark
M
Todd
Helen
H
Barbeau
Olivier
O
Quevedo
Camilo
C
Botfield
Hannah
H
Young
Rodrigo
R
Ruddle
Ruth
R
Samuel
Lee
L
Battersby
Alysia
A
Raynaud
Florence
F
Allen
Nicholas
N
Wilson
Stephen
S
Latinkic
Branko
B
Workman
Paul
P
McDonald
Edward
E
Blagg
Julian
J
Aherne
Wynne
W
Dale
Trevor
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D007739:L Cells; D051379:Mice; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis; D015027:Zebrafish
D000970:Antineoplastic Agents; D051153:Wnt Proteins