LGK-974

Catalog No.S7143 Synonyms: NVP-LGK974, WNT974

For research use only.

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. Phase 1.

LGK-974 Chemical Structure

CAS No. 1243244-14-5

Selleck's LGK-974 has been cited by 59 publications

Purity & Quality Control

Choose Selective PORCN Inhibitors

Biological Activity

Description 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. Phase 1.
Features Orally bioavailable Porcupine-specific inhibitor that has been tested in Phase I clinical trials for treatment of malignancies dependent on Wnt ligands.
Targets
Porcn [1]
(TM3 cells)
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]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
HPAF-II  Mof5S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NH3HSWgyKM7:TdMg NHS4ZZNFVVOR NWr1bpprcW6qaXLpeJMhfGinIHfyc5d1cCCxZjDwZY5kemWjdHnjJINidmOncjDj[YxtKGyrbnXzJJdqfGkEoGLOSlQ{dXW2YYTpc47DqA>? NXy3PIRNRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkO4OFczODNpPkKzPFQ4OjB|PD;hQi=>
PaTu 8988S  NWH6blM3T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NVXwToE4OSEQvF5CpC=> M4rsOWROW09? NXX2UJR2cW6qaXLpeJMhfGinIHfyc5d1cCCxZjDwZY5kemWjdHnjJINidmOncjDj[YxtKGyrbnXzJJdqfGkEoGLOSlQ{dXW2YYTpc47DqA>? MXm8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zOzh2N{KwN{c,OjN6NEeyNFM9N2F-
Capan-2 M{Sxcmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M2myN|Eh|ryPwrC= M{PN[mROW09? MUnpcohq[mm2czD0bIUh\3Kxd4ToJI9nKHCjbnPy[YF1cWNiY3HuZ4VzKGOnbHygcIlv\XNid3n0bOKhWk6INERCpI12fGG2aX;u NHy1RXY9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{M{i0O|IxOyd-MkO4OFczODN:L3G+
HPAF-II MWDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1vYeFEh|ryPwrC= NXPOcGVsTE2VTx?= MXrpcohq[mm2czD0bIUh\3Kxd4ToJI9nKHCjbnPy[YF1cWNiY3HuZ4VzKGOnbHygcIlv\XNid3n0bOKhWk6INERCpI12fGG2aX;u MX:8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zOzh2N{KwN{c,OjN6NEeyNFM9N2F-
PaTu8988S NUnnWVBmT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXTlbnYxOSEQvF5CpC=> MWHEUXNQ M136TYlvcGmkaYTzJJRp\SCpcn;3eIghd2ZicHHuZ5Jm[XSrYzDjZY5k\XJiY3XscEBtcW6nczD3bZRpyqCUTl[0N:KhdXW2YYTpc44> NH\zfVg9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{M{i0O|IxOyd-MkO4OFczODN:L3G+
293T  MlyySpVv[3Srb36gRZN{[Xl? MWHJR|UxyqCxZjCwMlQhdk1idH:gbY5pcWKrdIOgW451KHOrZ37hcIlv\yCrbjD0bIUh[W[xcnXt[Y51cW:wZXSgW451KGOxY4XseJVz\SCjc4PhfS=> NVv6NVhYRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkSyO|c5PTRpPkK0Nlc4QDV2PD;hQi=>
293T  MVLGeY5kfGmxbjDBd5NigQ>? MkHpTWM2OCCxZjCxJI5OKHSxIHPvcZBmfGVib3\mJHs{UF1vR17GMVE{OzFiaX6gZUBld3OnLXTldIVv\GWwdDDtZY5v\XJ? M{ezRlxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ2Mke3PFU1Lz5{NEK3O|g2PDxxYU6=
HT1080 MXPGeY5kfGmxbjDhd5NigQ>? NF7leY1KdmirYnn0bY9vKG:oIIDvdoN2eGmwZTDhZ5Rqfmm2eTCoeY5sdm:5bjDvdolocW5rIHX4dJJme3OnZDDpckBpfW2jbjDIWFExQDBiY3XscJMh[XO|ZYPz[YQh[XNic4XwdJJme3Orb36gc4YhX262M1GtcYVlcWG2ZXSgd5Vx\XJidH;wJIZt[XOqIHHjeIl3cXS7IHL5JHNVTiCudXPp[oVz[XOnIHHzd4F6NCCLQ{WwJF0hOC5yMEC0JO69VS5? M1vtd|xiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ4NUKyPVQ3Lz5{NkWyNlk1PjxxYU6=
L Wnt3A, HEK293 M2fTeWZ2dmO2aX;uJIF{e2G7 MkjWOFghcHK| MWPJcohq[mm2aX;uJI9nKFewdDDzbYdv[WyrbnegLJVvc26xd36gc5Jq\2mwKTDlfJBz\XO|ZXSgbY4hdW:3c3WgUEBYdnR|QTDj[YxteyClbz3jeYx1fXKnZDD3bZRpKEiHS{K5N{Bk\WyuczDh[pRmeiB2ODDodpMh[nliU4Xw[ZIufG:yIH\sZZNpKHKncH;yeIVzKGenbnWgZZN{[XluIFnDOVAhRSByLkCwNFkh|ryPLh?= NEnwb4I9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{Nk[0O|MxOyd-Mk[2OFc{ODN:L3G+
L Wnt3A, HEK293 MlXoSpVv[3Srb36gZZN{[Xl? NV[xcHY6PDhiaILz M1m3RWlvcGmkaYTpc44hd2ZicH;yZ5VxcW6nIHnuJI1wfXOnIFygW451O0FiY3XscJMh[29vY4XseJVz\WRid3n0bEBJTUt{OUOgZ4VtdHNiYX\0[ZIhPDhiaILzJIJ6KFO3cHXyMZRweCCobHHzbEBz\XCxcoTldkBo\W6nIHHzd4F6NCCLQ{WwJF0hOC5yMEC5JO69VS5? NXPRS3Y3RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMke2PVI2ODlpPkK3OlkzPTB7PD;hQi=>
L Wnt3A, HEK293 M3Pr[mZ2dmO2aX;uJIF{e2G7 MYS0PEBpenN? MW\Jcohq[mm2aX;uJI9nKHCxcnP1dIlv\SCrbjDtc5V{\SCOIGfueFNCKGOnbHzzJINwNWO3bIT1doVlKHerdHigTGVMOjl|IHPlcIx{KGG|c3Xzd4VlKGG|IIP1dJBz\XO|aX;uJI9nKFewdDDzbYdv[WyrbnegZYZ1\XJiNEigbJJ{KGK7IGP1dIVzNXSxcDDmcIF{cCC{ZYDvdpRmeiCpZX7lJIF{e2G7LDDJR|UxKD1iMD6wNFA6KM7:TT6= NXjmUWEzRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkm0PVk1QDNpPkK5OFk6PDh|PD;hQi=>
HEK293T Ml:5SpVv[3Srb36gZZN{[Xl? NVzENoJXOC5zIIXN MXO0PEBpenN? MkfBTY5pcWKrdHnvckBw\iCyb4LjeZBqdmViKIXub45wf25ib4Lp[4lvMSCrbjDISWszQTOWIHPlcIx{KHS{YX7z[oVkfGWmIIfpeIgheEyrYnnuMXdPXDODIIDsZZNucWRiYYPz[ZN{\WRiYYOgdoVlfWO2aX;uJIlvKFewdEPBJJNm[3KndHnvckBqdnSxIHPlcIwh[3WudIXy[UBu\WSrdX2gZZQhOC5zIIXNJIFnfGW{IES4JIhzeyCkeTDX[ZN1\XKwIHLsc5QhfGWlaH7pdZVm MY[8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPjZ2N{OwN{c,OjZ4NEezNFM9N2F-
HEK293T MlzKSpVv[3Srb36gZZN{[Xl? MnX3NE4yKHWP M3;UdVQ5KGi{cx?= MYXJcohq[mm2aX;uJI9nKHCxcnP1dIlv\SCrbjDISWszQTOWIHPlcIx{KHS{YX7z[oVkfGWmIIfpeIgheEyrYnnuMXdPXDODIIDsZZNucWRiYYPz[ZN{\WRiYYOgdoVlfWO2aX;uJIlvKFewdEPBJJNm[3KndHnvckBqdnSxIHPlcIwh[3WudIXy[UBu\WSrdX2gZZQhOC5zIIXNJIFnfGW{IES4JIhzeyCkeTDX[ZN1\XKwIHLsc5QhdWW2aH;k NWnUXFJ3RGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMke2PVI2ODlpPkK3OlkzPTB7PD;hQi=>
BT-12 Mn\WdWhVWyCjc4PhfS=> NV32WI41eUiWUzDv[kBx\WSrYYTybYMh[2GwY3XyJINmdGxibHnu[ZMhfG9iaXTlcpRq\nlibYXseIlxdGVib4Dwc5J1fW6rdHnld{Bnd3JiZIL1[{Bz\XC3coDvd4lv\zpiUILpcYFzgSC|Y4Ll[Y4h\m:{IFLUMVEzKGOnbHzz NHjyNmI9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{OUSzOVE{QSd-Mkm0N|UyOzl:L3G+
NB1643 NXzwWlE5eUiWUzDhd5NigQ>? M1vQVJFJXFNib3[gdIVlcWG2cnnjJINidmOncjDj[YxtKGyrbnXzJJRwKGmmZX70bYZ6KG23bITpdIxmKG:ycH;yeJVvcXSrZYOg[o9zKGS{dXegdoVxfXKyb4Ppcoc7KFC{aX3hdpkhe2O{ZXXuJIZweiCQQkG2OFMh[2WubIO= NIX1bGk9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{OUSzOVE{QSd-Mkm0N|UyOzl:L3G+
OHS-50 NUHsSo5teUiWUzDhd5NigQ>? M2LMc5FJXFNib3[gdIVlcWG2cnnjJINidmOncjDj[YxtKGyrbnXzJJRwKGmmZX70bYZ6KG23bITpdIxmKG:ycH;yeJVvcXSrZYOg[o9zKGS{dXegdoVxfXKyb4Ppcoc7KFC{aX3hdpkhe2O{ZXXuJIZweiCRSGOtOVAh[2WubIO= NGi1VGc9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{OUSzOVE{QSd-Mkm0N|UyOzl:L3G+
SK-N-MC MVzxTHRUKGG|c3H5 NHXWTJFyUFSVIH;mJJBm\GmjdILpZ{Bk[W6lZYKgZ4VtdCCuaX7ld{B1dyCrZHXueIlngSCvdXz0bZBt\SCxcIDvdpR2dmm2aXXzJIZweiCmcoXnJJJmeHW{cH;zbY5oQiCScnntZZJ6KHOlcnXlckBnd3JiU1utUk1OSyClZXzsdy=> MVq8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR|NUGzPUc,Ojl2M{WxN|k9N2F-
HEK293 MYXGeY5kfGmxbjDhd5NigQ>? MmfSNVAxKG6P NFjmc4I1QCCqcoO= NUW0SZZCUW6qaXLpeIlwdiCxZjDwc5JkfXCrbnWgbY4hUEWNMkmzJINmdGy|IITyZY5{\mWldHXkJJdqfGhicFzpZolvNVeQVEPBJJBt[XOvaXSgZZN{\XO|ZXSgZZMh\G:5boLl[5Vt[XSrb36gc4YhVFKSNjDwbI9{eGixconsZZRqd25iYYSgNVAxKG6PIHHmeIVzKDR6IHjyd{BjgSCZZYP0[ZJvKGKub4SgZY5idHm|aYO= NHvINJQ9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{OUS5PVQ5Oyd-Mkm0PVk1QDN:L3G+
HEK293T M1PqeWZ2dmO2aX;uJIF{e2G7 NXW5eIpEOTByIH7N M3zHWVQ5KGi{cx?= NEHDeG1KdmirYnn0bY9vKG:oIIDvdoN2eGmwZTDpckBJTUt{OUPUJINmdGy|IITyZY5{\mWldHXkJJdqfGhicFzpZolvNVeQVEPBJJBt[XOvaXSgZZN{\XO|ZXSgZZMhemWmdXP0bY9vKGmwIGfueFNCKHOnY4LleIlwdiCrboTvJINmdGxiY4XseJVz\SCvZXTpeY0h[XRiMUCwJI5OKGGodHXyJFQ5KGi{czDifUBY\XO2ZYLuJIJtd3RibXX0bI9l M1\5XVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ7NEm5OFg{Lz5{OUS5PVQ5OzxxYU6=
PA1 M1e0VmZ2dmO2aX;uJIF{e2G7 M4LvWVI1KGi{cx?= NUDQUItMUW6qaXLpeIlwdiCxZjDwc5JkfXCrbnWtcYVlcWG2ZXSgW451N2KndHGtZ4F1\W6rbjDzbYdv[WyrbnegbY4hcHWvYX6gVGEyKGOnbHzzJIF{e2W|c3XkJIF{KGSxd37y[Yd2dGG2aX;uJI9nKEG6aX6yJI1TVkFiZYjwdoV{e2mxbjDh[pRmeiB{NDDodpMh[nlicnXhcE11cW2nIGDDVkBidmGueYPpdy=> MnvyQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjl2OUm0PFMoRjJ7NEm5OFg{RC:jPh?=
HEK293 M4TtN2Z2dmO2aX;uJIF{e2G7 M4f5WVExOCCwTR?= NUe0eIhsPDhiaILz NG[0UGVKdmirYnn0bY9vKG:oIIDvdoN2eGmwZTDpckBJTUt{OUOgZ4VtdHNidILhcpNn\WO2ZXSge4l1cCCyTHnibY4uX06WM1GgdIxie22rZDDhd5Nme3OnZDDhd{Bld3ewcnXneYxifGmxbjDv[kBlcXOqZY\lcIVlKDJicHjvd5Bpd3K7bHH0bY9vKGG2IEGwNEBvVSCjZoTldkA1QCCqcoOgZpkhX2W|dHXyckBjdG:2IHHuZYx6e2m| Ml2zQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjl2OUm0PFMoRjJ7NEm5OFg{RC:jPh?=
Assay
Methods Test Index PMID
Western blot Nrf2 / Wnt3A / HO-1 / NQO-1 / Survivin ; NF-κB / IκB / p-IκB ; p-LRP6 / Axin / p-GSK3β / p-β-catenin / β-catenin 28627706 28128299
Immunofluorescence α1, 6-fucosylation ; FUT8 ; beta-catenin 28798691 25639201
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]

Protocol (from reference)

Cell Research:

[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 Research:

[1]

  • 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

Solubility (25°C)

In vitro

In vivo

Add solvents to the product individually and in order
(Data is from Selleck tests instead of citations):
2% DMSO+corn oil
For best results, use promptly after mixing.

5mg/mL

Chemical Information

Molecular Weight 396.44
Formula

C23H20N6O

CAS No. 1243244-14-5
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles CC1=CC(=CN=C1C2=CC(=NC=C2)C)CC(=O)NC3=NC=C(C=C3)C4=NC=CN=C4

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)

mg/kg g μL

Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

Calculation results:

Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

Molarity Calculator

Mass Concentration Volume Molecular Weight

Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT01351103 Recruiting Drug: LGK974|Biological: PDR001 Pancreatic Cancer|BRAF Mutant Colorectal Cancer|Melanoma|Triple Negative Breast Cancer|Head and Neck Squamous Cell Cancer|Cervical Squamous Cell Cancer|Esophageal Squamous Cell Cancer|Lung Squamous Cell Cancer Novartis Pharmaceuticals|Novartis December 1 2011 Phase 1

(data from https://clinicaltrials.gov, updated on 2022-08-01)

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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Frequently Asked Questions

Question 1:
If LGK974 is a lipophilic or hydrophilic substance?

Answer:
LGK974 is a lipophilic compound.

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