LGK974

• CAT Number: I000965
• CAS Number: 1243244-14-5
• Molecular Formula: C₂₃H₂₀N₆O
• Molecular Weight: 396.44
• Purity: ≥95%
• Target: Wnt/β-catenin
• Solubility: DMSO: ≥ 36 mg/mL
• Storage: Store at -20 C
• IC50: 0.4 nM [1]
• InChI: InChI=1S/C23H20N6O/c1-15-9-17(12-28-23(15)18-5-6-25-16(2)10-18)11-22(30)29-21-4-3-19(13-27-21)20-14-24-7-8-26-20/h3-10,12-14H,11H2,1-2H3,(H,27,29,30)
• InChIKey: XXYGTCZJJLTAGH-UHFFFAOYSA-N
• SMILES: CC1=C(N=CC(=C1)CC(=O)NC2=NC=C(C=C2)C3=NC=CN=C3)C4=CC(=NC=C4)C

LGK-974 is a potent and specific PORCN inhibitor, and inhibits Wnt signaling with IC50 of 0.4 nM.IC50 value: 0.4 nM [1]Target: Porcupinein vitro: LGK974 effectively displaces [3H]-GNF-1331 with IC50 of 1 nM in the PORCN radioligand binding assay, and shows no major cytotoxicity in cells up to 20 μM. LGK974 shows comparable inhibitory activities against all tested Wnts with IC50 ranging from 0.05 to 2.4 nM, which is consistent with the genetic loss of PORCN phenotype [1]. LGK974 specifically inhibits the growth of three RNF43-mutant cell lines, HPAF-II, PaTu 8988S, and Capan-2 [2].in vivo: In a murine MMTV-Wnt1 tumor model and a human head and neck squamous cell carcinoma model (HN30), LGK974 (3 mg/kg) inhibits Wnt signaling in vivo and induces tumor regression without significant body weight loss in the mice [1]. LGK974 (5 mg/kg, p.o., BID) also inhibits tumor growth of RNF43-mutant pancreatic tumors (HPAF-II and Capan-2) in vivo [2].

Reference

1:LPS-induced inflammatory response is suppressed by Wnt inhibitors, Dickkopf-1 and LGK974. Jang J, Jung Y, Kim Y, Jho EH, Yoon Y.Sci Rep. 2017 Jan 27;7:41612. doi: 10.1038/srep41612. PMID: 28128299 Free PMC Article2:Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T, Kasibhatla S, Schuller AG, Li AG, Cheng D, Li J, Tompkins C, Pferdekamper A, Steffy A, Cheng J, Kowal C, Phung V, Guo G, Wang Y, Graham MP, Flynn S, Brenner JC, Li C, Villarroel MC, Schultz PG, Wu X, McNamara P, Sellers WR, Petruzzelli L, Boral AL, Seidel HM, McLaughlin ME, Che J, Carey TE, Vanasse G, Harris JL.Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20224-9. doi: 10.1073/pnas.1314239110. Epub 2013 Nov 25. PMID: 24277854 Free PMC Article