LGK-974 1243244-14-5

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Molecular Weight:

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


Biological Activity


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. LGK974
specifically inhibits the growth of three RNF43-mutant cell lines,
HPAF-II, PaTu 8988S, and Capan-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. LGK974 (5 mg/kg, p.o., BID) also inhibits tumor growth of
RNF43-mutant pancreatic tumors (HPAF-II and Capan-2) in vivo.


Protocol(Only for Reference)


Cell Assay:


[2]

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 humidified atmosphere containing 5% CO2. Cells are fixed with final 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 Study:


[1]

Animal Models	A murine MMTV-Wnt1 tumor model and a human head and neck squamous cell carcinoma model (HN30)
Formulation	10% (vol/vol) citrate buffer (pH 2.8)/90% (vol/vol) citrate buffer (pH 3.0) or 0.5% MC/0.5% Tween 80
Dosages	~3 mg/kg daily
Administration	Oral gavage

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Baboon	Dog	Monkey	Rabbit	Guinea pig	Rat	Hamster	Mouse
Weight (kg)	12	10	3	1.8	0.4	0.15	0.08	0.02
Body Surface Area (m2)	0.6	0.5	0.24	0.15	0.05	0.025	0.02	0.007
Km factor	20	20	12	12	8	6	5	3

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×	mouse Km(3)	= 11.2 mg/kg
	rat Km(6)

Chemical Information

Molecular Weight (MW)	396.44
Formula	C23H20N6O
CAS No.	1243244-14-5

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms	N/A

Solubility (25°C) *	In vitro	DMSO	79 mg/mL heating (199.27 mM)
		Water	<1 mg/mL (
		Ethanol	<1 mg/mL (
* <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.

Chemical Name	[2,4'-Bipyridine]-5-acetamide, 2',3-dimethyl-N-[5-(2-pyrazinyl)-2-pyridinyl]-

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Product Categories : Cytoskeletal Signaling > Wnt/beta-catenin Inhibitor