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 58 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  MX7Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MWqxJO69VcLi Mk\HSG1UVw>? M{LtVYlvcGmkaYTzJJRp\SCpcn;3eIghd2ZicHHuZ5Jm[XSrYzDjZY5k\XJiY3XscEBtcW6nczD3bZRpyqCUTl[0N412fGG2aX;uxsA> MoKwQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjN6NEeyNFMoRjJ|OES3NlA{RC:jPh?=
PaTu 8988S  NFW1cGNIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NYrzPXZoOSEQvF5CpC=> M2rpZmROW09? NFSxNFhqdmirYnn0d{B1cGViZ4Lve5RpKG:oIIDhcoNz\WG2aXOgZ4Fv[2W{IHPlcIwhdGmwZYOge4l1cMLiUl7GOFNufXSjdHnvcuKh NWTuT2NQRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkO4OFczODNpPkKzPFQ4OjB|PD;hQi=>
Capan-2 NUTnb5RST3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1rkZ|Eh|ryPwrC= MWfEUXNQ M4rKSIlvcGmkaYTzJJRp\SCpcn;3eIghd2ZicHHuZ5Jm[XSrYzDjZY5k\XJiY3XscEBtcW6nczD3bZRpyqCUTl[0N:KhdXW2YYTpc44> NFHiTpM9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{M{i0O|IxOyd-MkO4OFczODN:L3G+
HPAF-II NGH5SJpIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NUGwN2VCOSEQvF5CpC=> NVPN[mhHTE2VTx?= NH\UPIpqdmirYnn0d{B1cGViZ4Lve5RpKG:oIIDhcoNz\WG2aXOgZ4Fv[2W{IHPlcIwhdGmwZYOge4l1cMLiUl7GOFPDqG23dHH0bY9v NGjYUFc9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{M{i0O|IxOyd-MkO4OFczODN:L3G+
PaTu8988S MYTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MnO5NUDPxE4EoB?= MXzEUXNQ Ml\hbY5pcWKrdIOgeIhmKGe{b4f0bEBw\iCyYX7jdoVifGmlIHPhcoNmeiClZXzsJIxqdmW|IIfpeIjDqFKQRkSzxsBufXSjdHnvci=> NITIXmU9[SC2YYLn[ZQ:L1:kbHHub{chcHKnZk2nbJR1eHN8Lz;weYJu\WRwbnPibU5vdG1wbnnoModwfi9{M{i0O|IxOyd-MkO4OFczODN:L3G+
293T  M1PjemZ2dmO2aX;uJGF{e2G7 NV\ObYhyUUN3MNMgc4YhOC52IH7NJJRwKGmwaHnibZR{KFewdDDzbYdv[WyrbnegbY4hfGinIHHmc5JmdWWwdHnvcoVlKFewdDDjc4N2dHS3cnWgZZN{[Xl? NXLmNJBGRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkSyO|c5PTRpPkK0Nlc4QDV2PD;hQi=>
293T  MnLPSpVv[3Srb36gRZN{[Xl? M{Kw[mlEPTBib3[gNUBvVSC2bzDjc41x\XSnIH;m[kBcO0ifLVfOSk0yOzNzIHnuJIEh\G:|ZT3k[ZBmdmSnboSgcYFvdmW{ MmWxQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjR{N{e4OVQoRjJ2Mke3PFU1RC:jPh?=
HT1080 NUnoZ2RMTnWwY4Tpc44h[XO|YYm= NYHwfXhkUW6qaXLpeIlwdiCxZjDwc5JkfXCrbnWgZYN1cX[rdImgLJVvc26xd36gc5Jq\2mwKTDlfJBz\XO|ZXSgbY4hcHWvYX6gTHQyODhyIHPlcIx{KGG|c3Xzd4VlKGG|IIP1dJBz\XO|aX;uJI9nKFewdEPBMY1m\GmjdHXkJJN2eGW{IITvdEBndGG|aDDhZ5Rqfmm2eTDifUBUXEZibIXjbYZmemG|ZTDhd5NigSxiSVO1NEA:KDBwMECwOEDPxE1w M2\2b|xiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ4NUKyPVQ3Lz5{NkWyNlk1PjxxYU6=
L Wnt3A, HEK293 MVjGeY5kfGmxbjDhd5NigQ>? NX\yS4M3PDhiaILz NEHZe2pKdmirYnn0bY9vKG:oIGfueEB{cWewYXzpcochMHWwa37ve44hd3KrZ3nuLUBmgHC{ZYPz[YQhcW5ibX;1d4UhVCCZboSzRUBk\WyuczDjc{1kfWy2dYLl[EB4cXSqIFjFT|I6OyClZXzsd{Bi\nSncjC0PEBpenNiYomgV5Vx\XJvdH;wJIZt[XOqIILldI9zfGW{IHflcoUh[XO|YYmsJGlEPTBiPTCwMlAxODlizszNMi=> M32wZVxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ4NkS3N|A{Lz5{Nk[0O|MxOzxxYU6=
L Wnt3A, HEK293 M1Hs[GZ2dmO2aX;uJIF{e2G7 NWnWdmloPDhiaILz NWXCTFAzUW6qaXLpeIlwdiCxZjDwc5JkfXCrbnWgbY4hdW:3c3WgUEBYdnR|QTDj[YxteyClbz3jeYx1fXKnZDD3bZRpKEiHS{K5N{Bk\WyuczDh[pRmeiB2ODDodpMh[nliU4Xw[ZIufG:yIH\sZZNpKHKncH;yeIVzKGenbnWgZZN{[XluIFnDOVAhRSByLkCwNFkh|ryPLh?= NVXHRpFoRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMke2PVI2ODlpPkK3OlkzPTB7PD;hQi=>
L Wnt3A, HEK293 Mn7ESpVv[3Srb36gZZN{[Xl? MXe0PEBpenN? NUG0[GQ4UW6qaXLpeIlwdiCxZjDwc5JkfXCrbnWgbY4hdW:3c3WgUEBYdnR|QTDj[YxteyClbz3jeYx1fXKnZDD3bZRpKEiHS{K5N{Bk\WyuczDhd5Nme3OnZDDhd{B{fXCycnXzd4lwdiCxZjDXcpQhe2mpbnHsbY5oKGGodHXyJFQ5KGi{czDifUBUfXCncj30c5Ah\myjc3igdoVxd3K2ZYKg[4Vv\SCjc4PhfUwhUUN3MDC9JFAvODByOTFOwG0v MXe8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR7OUS4N{c,Ojl2OUm0PFM9N2F-
HEK293T NUXzcldPTnWwY4Tpc44h[XO|YYm= Ml7TNE4yKHWP NGD3dFQ1QCCqcoO= NXKw[ZhYUW6qaXLpeIlwdiCxZjDwc5JkfXCrbnWgLJVvc26xd36gc5Jq\2mwKTDpckBJTUt{OUPUJINmdGy|IITyZY5{\mWldHXkJJdqfGhicFzpZolvNVeQVEPBJJBt[XOvaXSgZZN{\XO|ZXSgZZMhemWmdXP0bY9vKGmwIGfueFNCKHOnY4LleIlwdiCrboTvJINmdGxiY4XseJVz\SCvZXTpeY0h[XRiMD6xJJVOKGGodHXyJFQ5KGi{czDifUBY\XO2ZYLuJIJtd3RidHXjbI5qeXWn MWe8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zPjZ2N{OwN{c,OjZ4NEezNFM9N2F-
HEK293T NX[wUoV2TnWwY4Tpc44h[XO|YYm= MYSwMlEhfU1? NETrPWc1QCCqcoO= NVPp[FliUW6qaXLpeIlwdiCxZjDwc5JkfXCrbnWgbY4hUEWNMkmzWEBk\WyuczD0doFve2[nY4Tl[EB4cXSqIIDMbYJqdi2ZTmSzRUBxdGG|bXnkJIF{e2W|c3XkJIF{KHKnZIXjeIlwdiCrbjDXcpQ{SSC|ZXPy[ZRqd25iaX70c{Bk\WyuIHP1cJR2emVibXXkbZVuKGG2IECuNUB2VSCjZoTldkA1QCCqcoOgZpkhX2W|dHXyckBjdG:2IH3leIhw\A>? MnPEQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjd4OUK1NFkoRjJ5NkmyOVA6RC:jPh?=
BT-12 NWPaTI9FeUiWUzDhd5NigQ>? M2PCUpFJXFNib3[gdIVlcWG2cnnjJINidmOncjDj[YxtKGyrbnXzJJRwKGmmZX70bYZ6KG23bITpdIxmKG:ycH;yeJVvcXSrZYOg[o9zKGS{dXegdoVxfXKyb4Ppcoc7KFC{aX3hdpkhe2O{ZXXuJIZweiCEVD2xNkBk\Wyucx?= NVzYUlAxRGFidHHy[4V1RSehYnzhcosoKGi{ZX[9K4h1fHC|Oj:vdJVjdWWmLn7jZokvdmyvLn7pbE5od3ZxMkm0N|UyOzlpPkK5OFM2OTN7PD;hQi=>
NB1643 NH[5fndyUFSVIHHzd4F6 NF\HSlRyUFSVIH;mJJBm\GmjdILpZ{Bk[W6lZYKgZ4VtdCCuaX7ld{B1dyCrZHXueIlngSCvdXz0bZBt\SCxcIDvdpR2dmm2aXXzJIZweiCmcoXnJJJmeHW{cH;zbY5oQiCScnntZZJ6KHOlcnXlckBnd3JiTlKxOlQ{KGOnbHzz M1nrNlxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ7NEO1NVM6Lz5{OUSzOVE{QTxxYU6=
OHS-50 NWeySVB4eUiWUzDhd5NigQ>? M2LTOJFJXFNib3[gdIVlcWG2cnnjJINidmOncjDj[YxtKGyrbnXzJJRwKGmmZX70bYZ6KG23bITpdIxmKG:ycH;yeJVvcXSrZYOg[o9zKGS{dXegdoVxfXKyb4Ppcoc7KFC{aX3hdpkhe2O{ZXXuJIZweiCRSGOtOVAh[2WubIO= MkDTQIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjl2M{WxN|koRjJ7NEO1NVM6RC:jPh?=
SK-N-MC MkDhdWhVWyCjc4PhfS=> M2DHWJFJXFNib3[gdIVlcWG2cnnjJINidmOncjDj[YxtKGyrbnXzJJRwKGmmZX70bYZ6KG23bITpdIxmKG:ycH;yeJVvcXSrZYOg[o9zKGS{dXegdoVxfXKyb4Ppcoc7KFC{aX3hdpkhe2O{ZXXuJIZweiCVSz3OMW1EKGOnbHzz Mor5QIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjl2M{WxN|koRjJ7NEO1NVM6RC:jPh?=
HEK293 MUDGeY5kfGmxbjDhd5NigQ>? NYjZNlRNOTByIH7N MmnYOFghcHK| M3T0ZmlvcGmkaYTpc44hd2ZicH;yZ5VxcW6nIHnuJGhGUzJ7MzDj[YxteyC2cnHud4Zm[3SnZDD3bZRpKHCOaXLpck1YVlR|QTDwcIF{dWmmIHHzd4V{e2WmIHHzJIRwf26{ZXf1cIF1cW:wIH;mJGxTWDZicHjvd5Bpd3K7bHH0bY9vKGG2IEGwNEBvVSCjZoTldkA1QCCqcoOgZpkhX2W|dHXyckBjdG:2IHHuZYx6e2m| MmD3QIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjl2OUm0PFMoRjJ7NEm5OFg{RC:jPh?=
HEK293T MnnXSpVv[3Srb36gZZN{[Xl? NWWy[ppMOTByIH7N NVvlOI9oPDhiaILz M2nP[GlvcGmkaYTpc44hd2ZicH;yZ5VxcW6nIHnuJGhGUzJ7M2SgZ4VtdHNidILhcpNn\WO2ZXSge4l1cCCyTHnibY4uX06WM1GgdIxie22rZDDhd5Nme3OnZDDhd{Bz\WS3Y4Tpc44hcW5iV370N2Ehe2WlcnX0bY9vKGmwdH:gZ4VtdCCldXz0eZJmKG2nZHn1cUBifCBzMECgcm0h[W[2ZYKgOFghcHK|IHL5JHdme3Sncn6gZoxwfCCvZYToc4Q> MlS3QIEhfGG{Z3X0QUdg[myjbnunJIhz\WZ;J3j0eJB{Qi9xcIXicYVlNm6lYnmucoxuNm6raD7nc5YwOjl2OUm0PFMoRjJ7NEm5OFg{RC:jPh?=
PA1 MoPWSpVv[3Srb36gZZN{[Xl? NELme2EzPCCqcoO= MYHJcohq[mm2aX;uJI9nKHCxcnP1dIlv\S2vZXTpZZRm\CCZboSvZoV1[S2lYYTlcolvKHOrZ37hcIlv\yCrbjDoeY1idiCSQUGgZ4VtdHNiYYPz[ZN{\WRiYYOg[I94dnKnZ4XsZZRqd25ib3[gRZhqdjJibWLORUBmgHC{ZYPzbY9vKGGodHXyJFI1KGi{czDifUBz\WGuLYTpcYUhWEOUIHHuZYx6e2m| M3;helxiKHSjcnfleF0oZ2KuYX7rK{BpemWoPTfoeJRxezpxL4D1Zo1m\C6wY3LpMo5tdS6waXiu[493NzJ7NEm5OFg{Lz5{OUS5PVQ5OzxxYU6=
HEK293 MU\GeY5kfGmxbjDhd5NigQ>? Mm\VNVAxKG6P MkPwOFghcHK| MVrJcohq[mm2aX;uJI9nKHCxcnP1dIlv\SCrbjDISWszQTNiY3XscJMhfHKjboPm[YN1\WRid3n0bEBxVGmkaX6tW25VO0FicHzhd41q\CCjc4Pld5Nm\CCjczDkc5dvemWpdXzheIlwdiCxZjDkbZNp\X[nbHXkJFIheGixc4Doc5J6dGG2aX;uJIF1KDFyMDDuUUBi\nSncjC0PEBpenNiYomgW4V{fGW{bjDicI91KGGwYXz5d4l{ MWi8ZUB1[XKpZYS9K39jdGGwazegbJJm\j1paIT0dJM7Ny:ydXLt[YQvdmOkaT7ucI0vdmmqLnfvek8zQTR7OUS4N{c,Ojl2OUm0PFM9N2F-
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

DMSO 79 mg/mL warmed
(199.27 mM)
Water Insoluble
Ethanol Insoluble

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 2022-01-17)

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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