LGK-974

Description

Description

LGK-974 is a potent and specific PORCN inhibitor, and inhibits Wnt signaling with IC50 of 0.4 nM. Phase 1.

In 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 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]

Orally bioavailable EZH2-selective inhibitor that has been tested in Phase I clinical trials for treatment of malignancies dependent on Wnt ligands.

LGK-974

Catalog No.S7143

LGK-974 is a potent and specific PORCN inhibitor, and inhibits Wnt signaling with IC50 of 0.4 nM. Phase 1.

Size

Price

Stock

Quantity

5mg	USD 311	In stock	0 1 2 3 4 5 6 7 8 9 10
50mg	USD 1222	In stock	0 1 2 3 4 5 6 7 8 9 10

Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw

Cell lines	HPAF-II, PaTu 8988S, and Capan-2 cells
Concentrations	~1 μM
Incubation Time	3 days
Method	Cells are plated in growth medium in a 96-well plate at a density of 6,000–12,000 cells per well and treated with DMSO or 1 μM LGK974. After 3 d, the cells are treated with fresh growth medium containing 20 μM EdU, which is included in the Click-iT EdU Alexa Fluor 488 HCS assay kit, and the plate was incubated for 2 h at 37 °C in a humidiï¬ed atmosphere containing 5% CO₂. Cells are ï¬xed with ï¬nal 4% (mass/vol) paraformaldehyde for 30 min, washed with PBS, permeabilized, and stained with 50 μg/mL Hoechst in PBS for 30 min. After wash, the cells are proceeded to EdU detection according to the instruction of Click-iT EdU assay kit. Triplet wells are performed for each condition.

Animal Models	A murine MMTV-Wnt1 tumor model and a human head and neck squamous cell carcinoma model (HN30)
Dosages	~3 mg/kg daily
Administration	Oral gavage

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT01351103	Recruiting	Melanoma\|Breast Neoplasms\|Lobular Carcinoma\|Triple-negative Breast Cancer\|Pancreatic Adenocarcinoma	Novartis\|Novartis Pharmaceuticals	2011-12	Phase 1

Solubility (25°C) *	In vitro	DMSO	79 mg/mL (199 mM)
		Water	<1 mg/mL (<1 mM)
		Ethanol	<1 mg/mL (<1 mM)
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.