Wnt signaling is tightly controlled during cellular proliferation, differentiation and embryonic morphogenesis. Aberrant activation of this pathway plays a critical role in a variety of cancers. Blockade of Wnt signaling is therefore an attractive therapeutic approach for anticancer therapy.  In this presentation, we will discuss our approach to search for inhibitors of Wnt ligand secretion. We developed and performed a cellular high-throughput screen using a co-culture system. Lead structure (GNF-1331) was identified and further target elucidation revealed Porcupine, a membrane bound O-acyl transferase, as its molecular target.  Further structure-activity relationship studies led to the discovery of LGK974, a potent and specific Porcupine inhibitor. Treatment of LGK974 leads to tumor regression in a Wnt dependent MMTV-Wnt1 mouse model at well tolerated doses. LGK974 is currently in Phase 1 clinical trials.

Discovery of LGK974, a potent and selective Porcupine inhibitor targeting Wnt signaling

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.