LGK974 is a potent and orally active Wnt pathway inhibitor with an IC50<1 nM in the Wnt signaling assay [1]. It inhibits acylation of Wnt proteins by Porcupine (Porcn). LGK974 specifically blocks the proliferation of pancreatic cancer cells that have up-regulated Wnt signaling caused by carrying inactive mutations in a Ubiquitin E3 ligase, RNF43 [2].

LGK974 robustly suppressed Wnt signaling in vivo resulting in tumor regression in a murine breast cancer model driven by MMTV-Wnt1, and showed excellent efficacy in xenograft models of head and neck squamous cell carcinoma and pancreatic cancer [3]. Currently LGK974 is in the Phase I study to treat patients with different types of Wnt signaling-driven cancers [4].