WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205851
CAS#: 1243244-14-5 (free base)
Description: LGK974, also known as WNT974, is a selective and orally bioavailable porcupine (PORCN) inhibitor under development for the treatment of cancers that are driven by the Wnt pathway in a Wnt ligand-dependent manner. WNT974 binds to and inhibits PORCN in the endoplasmic reticulum (ER), which blocks post-translational acylation of Wnt ligands and inhibits their secretion. This prevents the activation of Wnt ligands, interferes with Wnt-mediated signaling, and inhibits cell growth in Wnt-driven tumors. Porcupine, a membrane-bound O-acyltransferase (MBOAT), is required for the palmitoylation of Wnt ligands, and plays a key role in Wnt ligand secretion and activity. Wnt signaling is dysregulated in a variety of cancers.
MedKoo Cat#: 205851
Name: LGK974
CAS#: 1243244-14-5 (free base)
Chemical Formula: C23H20N6O
Exact Mass: 396.16986
Molecular Weight: 396.44
Elemental Analysis: C, 69.68; H, 5.08; N, 21.20; O, 4.04
Related CAS #: 2375595-49-4 (2HCl) 1243244-14-5 (free base)
Synonym: LGK974; LGK-974; LGK 974; WNT974; WNT 974; WNT-974
IUPAC/Chemical Name: 2-(2',3-dimethyl-[2,4'-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide
InChi Key: XXYGTCZJJLTAGH-UHFFFAOYSA-N
InChi Code: 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)
SMILES Code: O=C(NC1=NC=C(C2=NC=CN=C2)C=C1)CC3=CN=C(C4=CC(C)=NC=C4)C(C)=C3
Appearance: white solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >5 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | LGK-974 (NVP-LGK974, WNT974) is a potent and specific PORCN inhibitor, and inhibits Wnt signaling with IC50 of 0.4 nM in TM3 cells. |
| In vitro activity: | Medicinal chemistry optimization of GNF-1331 was carried out to improve potency and pharmacokinetic properties. This effort led to the discovery of LGK974 (Fig. 1B), a highly specific and potent PORCN inhibitor. LGK974 effectively displaced [3H]-GNF-1331 with an IC50 of 1 nM in the PORCN radioligand binding assay (Fig. 1C and Fig. S1B). LGK974 also potently inhibited Wnt signaling in the aforementioned Wnt coculture assay with an IC50 of 0.4 nM (Fig. 1D). This inhibitory effect was rescued by the addition of exogenous Wnt3A CM (Fig. 1E). Additionally, LGK974 showed no major cytotoxicity in cells up to 20 µM (Fig. S1C). To further confirm the activity of LGK974 in blocking PORCN-dependent Wnt secretion, 293A cells were transfected with HA-tagged Wnt3A and treated with various doses of LGK974. As shown in Fig. 1F and Fig. S1D, LGK974 potently decreased levels of HA-Wnt3A in the supernatant with slightly increased levels of HA-Wnt3A in the cell lysate, suggesting that Wnt3A secretion was substantially inhibited by LGK974 in a dose-dependent manner. In Wnt-responsive cells, secreted Wnts cause phosphorylation of the Wnt coreceptor LRP6. In L-Wnt3A cells, a mouse cell line overexpressing Wnt3A, LGK974, strongly blocked Wnt-dependent phosphorylation of LRP6 (Fig. S1E). Reference: Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20224-9. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24277854/ |
| In vivo activity: | In a murine MMTV-Wnt1 tumor model using s.c. implanted tumor fragments derived from MMTV-Wnt1 transgenic mice, LGK974 exhibited strong dose-dependent efficacy when administered daily (Fig. 2A). Briefly, changes in tumor volume for each of the treated (T) and control (C) groups were measured and used to calculate growth delay as expressed by the T/C ratio. A dose of 0.3 mg/kg LGK974 led to tumor growth delay (T/C: 26%), whereas a dose of 1 or 3 mg/kg induced very significant tumor regression (T/C: −47% or −63%, respectively) on day 13 of treatment. As shown in Fig. S2A, the regimen was well-tolerated without significant body weight loss in the mice. Similar efficacy was observed with LGK974 in a murine MMTV-Wnt3 model (Fig. S2B). Reference: Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20224-9. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24277854/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 32.0 | 80.72 |
The following data is based on the product molecular weight 396.44 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| In vitro protocol: | 1. 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. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. 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; PMCID: PMC3864356. 2. Jiang X, Hao HX, Growney JD, Woolfenden S, Bottiglio C, Ng N, Lu B, Hsieh MH, Bagdasarian L, Meyer R, Smith TR, Avello M, Charlat O, Xie Y, Porter JA, Pan S, Liu J, McLaughlin ME, Cong F. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):12649-54. doi: 10.1073/pnas.1307218110. Epub 2013 Jul 11. PMID: 23847203; PMCID: PMC3732970. |
| In vivo protocol: | 1. 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. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. 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; PMCID: PMC3864356. 2. Jiang X, Hao HX, Growney JD, Woolfenden S, Bottiglio C, Ng N, Lu B, Hsieh MH, Bagdasarian L, Meyer R, Smith TR, Avello M, Charlat O, Xie Y, Porter JA, Pan S, Liu J, McLaughlin ME, Cong F. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):12649-54. doi: 10.1073/pnas.1307218110. Epub 2013 Jul 11. PMID: 23847203; PMCID: PMC3732970. |
1: 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. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20224-9. doi: 10.1073/pnas.1314239110. Epub 2013 Nov 25. PubMed PMID: 24277854; PubMed Central PMCID: PMC3864356.
2: Jiang X, Hao HX, Growney JD, Woolfenden S, Bottiglio C, Ng N, Lu B, Hsieh MH, Bagdasarian L, Meyer R, Smith TR, Avello M, Charlat O, Xie Y, Porter JA, Pan S, Liu J, McLaughlin ME, Cong F. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):12649-54. doi: 10.1073/pnas.1307218110. Epub 2013 Jul 11. PubMed PMID: 23847203; PubMed Central PMCID: PMC3732970.
