The Wnt signalling pathway is frequently deregulated in cancer due to mutations in APC, �-catenin and axin; indeed 80% of colon cancers have defects in the APC gene leading to high levels of �-catenin. Some colon cancers, endometrial cancers and melanomas that lack defects in the APC gene harbour �-catenin mutations that abrogate its degradation. We have screened a diverse small molecule chemical library against a cell-based luciferase reporter assay to identify small molecule inhibitors of Wnt signalling.1 Here we report the medicinal chemistry optimisation of a pyridine-based series of inhibitors resulting in the discovery of potent, selective and orally bioavailable small molecule inhibitors of Wnt signalling.References1. Ewan K, Pajak B, Stubbs M, Wildish H, Barbeau O, Camilo Q, Botfield H, Young R, Ruddle R, Samuel L, Battersby A, Raynaud F, Allen N, Wilson S, Laitinic B, Workman P, MacDonald E, Blagg J, Aherne W, Dale T (2010). A useful approach to identify novel inhibitors of Wnt-dependent transcription. Cancer Research, 70  , 5963-5973.

Discovery of potent small molecule inhibitors of Wnt-dependent transcription

248th National Meeting (2014)

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