LDE225 (NVP-LDE225,Erismodegib)

Catalog No.S2151

LDE225 (NVP-LDE225,Erismodegib) is a Smoothened (Smo) antagonist, inhibiting Hedgehog (Hh) signaling with IC50 of 1.3 nM (mouse) and 2.5 nM (human) in cell-free assays, respectively. Phase 3.

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LDE225 (NVP-LDE225,Erismodegib) Chemical Structure

LDE225 (NVP-LDE225,Erismodegib) Chemical Structure
Molecular Weight: 485.5

Validation & Quality Control

3 customer reviews :

Quality Control & MSDS

Related Compound Libraries

LDE225 (NVP-LDE225,Erismodegib) is available in the following compound libraries:

Hedgehog/Smoothened Inhibitors with Unique Features

  • Selective Smoothened inhibitor

    PF-5274857 Smoothened-selective, IC50=5.8 nM.

  • Smoothened Inhibitor in Clinical Trial

    LDE225 (NVP-LDE225,Erismodegib) Phase III for Hh-pathway activated relapsed Medulloblastoma (MB).

  • Newest Smoothened Inhibitor

    GANT61 Inhibitor for GLI1 as well as GLI2-induced transcription, inhibits hedgehog with IC50 of 5 μM, displays selectivity over other pathways, such as TNF and glucocorticoid receptor gene transactivation.

  • Smoothened Activator

    Purmorphamine Directly binds and activates Smoothened, and blocks BODIPY-cyclopamine binding to Smo with IC50 of ~ 1.5 μM.

Product Information

  • Compare Hedgehog/Smoothened Inhibitors
    Compare Hedgehog/Smoothened Products
  • Research Area
  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity

Description LDE225 (NVP-LDE225,Erismodegib) is a Smoothened (Smo) antagonist, inhibiting Hedgehog (Hh) signaling with IC50 of 1.3 nM (mouse) and 2.5 nM (human) in cell-free assays, respectively. Phase 3.
Targets Smo (mouse) [1]
(Cell-free assay)
Smo (human) [1]
(Cell-free assay)
IC50 1.3 nM 2.5 nM
In vitro LDE225 inhibits TM3 luciferized cell line with 0.6 nM and 8 nM, at the presence of 1 nM and 25 nM Hh agonist Ag1.5, respectively. [1]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
A2780ip2NUn2W3Z4S3m2b4jpZ4l1gSCjc4PhfS=>MkP5glExKM7:TR?=NX6wbIpOUUN3ME2xNkDPxE1?MV6yNlU2OzN3NR?=
A2780cp20NUPZdW9tS3m2b4jpZ4l1gSCjc4PhfS=>MlOxglExKM7:TR?=M4fxVGlEPTB;Nz61JO69VQ>?MVyyNlU2OzN3NR?=
SKOV3ip1M1fUNWN6fG:6aXPpeJkh[XO|YYm=NELaR|Z,OTBizszNNXfZOVV5UUN3ME2yOEDPxE1?NVnaZWM2OjJ3NUOzOVU>
SKOV3TRip2M2XIeWN6fG:6aXPpeJkh[XO|YYm=MkXrglExKM7:TR?=M1vHemlEPTB;MUKg{txONYTnc2N1OjJ3NUOzOVU>
HeyA8NUTCTmJqS3m2b4jpZ4l1gSCjc4PhfS=>NEn3N5N,OTBizszNNHPLUJNKSzVyPUG4JO69VQ>?MYiyNlU2OzN3NR?=
HeyA8MDRMl[2R5l1d3irY3n0fUBie3OjeR?=M3HxdZ4yOCEQvF2=MnnDTWM2OD16IN88US=>NIjVWokzOjV3M{O1OS=>
OS5MmT4S5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?NWX3S2RphjVizszNMY\y[YR2[2W|IITo[UBxem:uaX\ldoF1cW:wNXXkTmtTOjN{NEO1PVU>
OS18MVPHdo94fGhiaX7obYJqfG:{eTDhd5NigQ>?MlLVglUh|ryPM2\0[pJm\HWlZYOgeIhmKHC{b3zp[oVz[XSrb36=MXGyN|I1OzV7NR?=
Glioblastoma initiating cellsMmnLR5l1d3irY3n0fUBie3OjeR?=NEHxcnl,OTBizszNMWjJcohq[mm2czDD[YxtKF[rYXLpcIl1gQ>?MoLVNlM1QDJ4N{G=
Glioblastoma initiating cellsMXnGeY5kfGmxbjDhd5NigQ>?NILSPZN,OTBizszNM2rFbYlvcGmkaYTzJI5mfXKxc4Do[ZJmKG[xcn3heIlwdg>?MUKyN|Q5OjZ5MR?=
Glioblastoma initiating cellsNEnBWXJEgXSxeHnjbZR6KGG|c3H5NIPWV4V,OTBizszNMWDpcoR2[2W|IHHwc5B1d3Orcx?=NXjicFZOOjN2OEK2O|E>
Glioblastoma initiating cellsM1fScmZ2dmO2aX;uJIF{e2G7NFLYNJN,OTBizszNNVTuXmpw\G:5boLl[5Vt[XSnczD0bIUhW0iKIIPp[45idGmwZzDwZZRpf2G7NUfwdnVvOjN2OEK2O|E>
Glioblastoma initiating cellsNGfBOFlHfW6ldHnvckBie3OjeR?=MXL+NVAh|ryPNV[wbWxEUW6qaXLpeJMhfGinIFX4dJJme3Orb36gc4YhT2WwZYOgTY53d2y4ZXSgbY4hVWGrboThbY5qdmdiUHz1dolxd3SnbnP5NHnOR|gzOzR6Mk[3NS=>
Glioblastoma initiating cellsNX;2PXZzTnWwY4Tpc44h[XO|YYm=MXj+NVAh|ryPNWjrRWRMUW6qaXLpeJMhVW:2aXzpeJktKEmwdnHzbY9vNCCjbnSgUYloemG2aX;uM2fLdlI{PDh{Nkex
LOX IMVIMXLGeY5kfGmxbjDhd5NigQ>?MlTBNVAh|ryPMUDEUXNQMVvpcohq[mm2czDI[YRo\WixZz3HUGkheGG2aIfhfS=>M3LTUlI{QTN3OUK1
UACC 257MkfkSpVv[3Srb36gZZN{[Xl?NX\TUHQxOTBizszNMWLEUXNQNXraRXFXcW6qaXLpeJMhUGWmZ3Xoc4cuT0yLIIDheIh4[Xl?M{TEWlI{QTN3OUK1
LOX IMVIMnfXSpVv[3Srb36gZZN{[Xl?NFj6TGEyOCEQvF2=MnzoSG1UVw>?NFewTXBqdmS3Y3XzJGcyKGOnbHygZ5lkdGViYYLy[ZN1Mm\2NlM6OzV7MkW=
UACC 257MUnGeY5kfGmxbjDhd5NigQ>?NUmwcppkOTBizszNM{LSZ2ROW09?NIPN[oRqdmS3Y3XzJGcyKGOnbHygZ5lkdGViYYLy[ZN1MWOyN|k{PTl{NR?=
LOX IMVINXrlZnAyS3m2b4jpZ4l1gSCjc4PhfS=>M2C5[lExKM7:TR?=NHTtcndFVVORMoT6[IVkemWjc3XzJJR2dW:{IHPlcIwhfmmjYnnsbZR6MYOyN|k{PTl{NR?=
UACC 257MkXIR5l1d3irY3n0fUBie3OjeR?=M{XqPFExKM7:TR?=Mo\ySG1UVw>?NHGwZmZl\WO{ZXHz[ZMhfHWvb4KgZ4VtdCC4aXHibYxqfHl?NGPhWJYzOzl|NUmyOS=>
LOX IMVINH\IWGhCeG:ydH;zbZMh[XO|YYm=MXWxNEDPxE1?NX\NXYl{TE2VTx?=NHXkRppqdmS3Y3XzJIFxd3C2b4Ppdy=>MYiyN|k{PTl{NR?=
UACC 257NIr4NYRCeG:ydH;zbZMh[XO|YYm=M2npO|ExKM7:TR?=NYrISVhUTE2VTx?=M{\QOolv\HWlZYOgZZBweHSxc3nzMk\tNlM6OzV7MkW=
ACHNNFfCV5BIem:5dHigbY5pcWKrdH;yfUBie3OjeR?=NUXISlBihjVizszNMXfEUXNQMYXJR|UxRTJvM,MAje69VQ>?NXfyN5BOOjVyOUO0PVE>
769-PMmTUS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?M4D2d542KM7:TR?=NVP1T|RiTE2VTx?=NHn5OHVKSzVyPUKtN-KBkc7:TR?=Ml3UNlUxQTN2OUG=
786-OMorZS5Jwf3SqIHnubIljcXSxcomgZZN{[Xl?MYf+OUDPxE1?MlnLSG1UVw>?M2j4V2lEPTB;Mj2z5qCK|ryPMnL6NlUxQTN2OUG=
786-O SuRM{Tmc2dzd3e2aDDpcohq[mm2b4L5JIF{e2G7NX\iSZhShjVizszNNVrFbnhMTE2VTx?=NH\Yd2FKSzVyPUKtN-KBkc7:TR?=NEjReHQzPTB7M{S5NS=>
SP53MUTGeY5kfGmxbjDhd5NigQ>?MYOzNEDPxE1?NGDDcIpFVVORMV3pcohq[mm2czDj[YxtKGGmaHXzbY9vKGGwZDDtbYdz[XSrb36=NF7MepAzPjh6NU[wPC=>
SP53MWLGeY5kfGmxbjDhd5NigQ>?NVPodHZiOzBizszNM1\HbmROW09?NFXLdI1qdmirYnn0d{B1cGViVlzBOE1u\WSrYYTl[EBHSUtic3nncoFtcW6pIIDheIh4[Xl?MoXrNlY5QDV4MEi=
HS5MofZSpVv[3Srb36gZZN{[Xl?NUDFW2dIOzBizszNMVXEUXNQM3nkWYlvcGmkaYTzJINmdGxiYXTo[ZNqd25iYX7kJI1q\3KjdHnvci=>M{C3S|I3QDh3NkC4
HS27aM4P1WWZ2dmO2aX;uJIF{e2G7MmP0N|Ah|ryPMWDEUXNQMXnpcohq[mm2czDj[YxtKGGmaHXzbY9vKGGwZDDtbYdz[XSrb36=M{XJWFI3QDh3NkC4
SP53MniyR5l1d3irY3n0fUBie3OjeR?=M3GyT|MxKM7:TR?=MV7EUXNQNWT0epl5cW6mdXPld{BifXSxcHjh[5k>NE\LeGszPjh6NU[wPC=>
JekoMojDR5l1d3irY3n0fUBie3OjeR?=MVKzNEDPxE1?NX7hbmNXTE2VTx?=MYfpcoR2[2W|IHH1eI9xcGGpeR?=NITwXFUzPjh6NU[wPC=>

... Click to View More Cell Line Experimental Data

In vivo LDE225 is highly bound to mouse, rat, and human plasma proteins (>99%) and moderately bound to dog and monkey plasma proteins (77 and 85%, respectively). LDE225 has high permeability (90.8% in man) in the PAMPA assay. LDE225 shows good oral bioavailability ranging from 69 to 102% in preclinical species when dosed in solution. LDE225 is a weak base with a measured pKa of 4.20 and exhibits relatively poor aqueous solubility. LDE225 demonstrates dose-related antitumor activity. At a dose of 5 mg/kg/day qd, LDE225 significantly inhibits tumor growth, corresponding to a T/C value of 33%. When dosed at 10 and 20 mg/kg/day qd, LDE225 gives rise to 51 and 83% regression, respectively. Gli1 mRNA inhibition correlates with tumor and plasma exposure of LDE225. LDE225 successfully penetrates the blood−brain barrier in tumor-bearing animals and results in tumor growth inhibition after 4 days of treatment. [1] LDE225 significantly reduces the tumor volume by 95.7% in Rip1-Tag2 mice. LDE225 prolongs survival in Rip1Tag2 mice. LDE225 decreases expression of stromal markers in the LDE225-treated mice. [2]
Features

Protocol(Only for Reference)

Cell Assay: [1]

Cell lines TM3Hh12 cells
Concentrations ~10 μM
Incubation Time 30 minutes
Method LDE225 is prepared for assay by serial dilution in DMSO and then added to empty assay plates. TM3Hh12 cells (TM3 cells containing Hh-responsive reporter gene construct pTA-8xGli-Luc) are cultured in F12 Ham's/DMEM (1:1) containing 5% horse serum, 2.5% fetal bovine serum (FBS), and 15 mM HEPES, pH 7.3. Cells are harvested by trypsin treatment, resuspended in F12 Ham's/DMEM (1:1) containing 5% horse serum and 15 mM HEPES, pH 7.3, added to assay plates, and incubated with LDE225 for approximately 30 min at 37 °C in 5% CO2. Then 1 nM or 25 nM Ag1.5 is added to assay plates and incubated at 37 °C in the presence of 5% CO2. After 48 hours, either Bright-Glo or MTS reagent is added to the assay plates and luminescence or absorbance at 492 nm is determined. IC50 values, defined as the inflection point of the logistic curve, are determined by nonlinear regression of the Gli-driven luciferase luminescence or absorbance signal from MTS assay vs log10 (concentration) of LDE225 using the R statistical software pack

Animal Study: [1]

Animal Models Orthotopic Ptch+/-p53-/- medulloblastoma allograft model in athymic nude mice
Formulation 0.5% sodium carboxymethyl cellulose
Dosages 40 mg/kg/day
Administration Administered via p.o. or b.i.d

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

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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)
1

References

[1] Pan SF, et al. ACS Med. Chem. Lett., 2010, 1 (3), 130–134.

[2] Fendrich V, et al. Ann Surg, 2011, 254(5), 818-23.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-23)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02254551 Terminated Multiple Myeloma SCRI Development Innovations, LLC|Novartis January 2015 Phase 2
NCT02138929 Recruiting Esophageal Cancer M.D. Anderson Cancer Center|Novartis|National Cancer Inst  ...more M.D. Anderson Cancer Center|Novartis|National Cancer Institute (NCI) November 2014 Phase 1
NCT02195973 Recruiting Recurrent Ovarian Cancer University of Alabama at Birmingham|Novartis Pharmaceuticals September 2014 Phase 1
NCT02151864 Recruiting Hepatocellular Carcinoma|Cirrhosis Jason K. Sicklick, M.D.|Novartis Pharmaceuticals|Universi  ...more Jason K. Sicklick, M.D.|Novartis Pharmaceuticals|University of California, San Diego July 2014 Phase 1
NCT02182622 Not yet recruiting Prostate Cancer Martin Gutierrez|Novartis|Hackensack University Medical C  ...more Martin Gutierrez|Novartis|Hackensack University Medical Center July 2014 Phase 1

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Chemical Information

Download LDE225 (NVP-LDE225,Erismodegib) SDF
Molecular Weight (MW) 485.5
Formula

C26H26F3N3O3

CAS No. 956697-53-3
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms Sonidegib
Solubility (25°C) * In vitro DMSO 97 mg/mL (199.79 mM)
Ethanol 97 mg/mL warming (199.79 mM)
Water <1 mg/mL (<1 mM)
In vivo 2% DMSO+corn oil 10mg/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 [1,1'-Biphenyl]-3-carboxamide, N-[6-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-3-pyridinyl]-2-methyl-4'-(trifluoromethoxy)-, rel-

Customer Product Validation(3)


Click to enlarge
Rating
Source Nat Chem Biol 2013 9, 247-9. LDE225 (NVP-LDE225,Erismodegib) purchased from Selleck
Method Luciferase assay
Cell Lines NIH 3T3
Concentrations 10 μM
Incubation Time 24 h
Results Notably, addition of 10 μM RU-SKI 43 or LDE225, a Smoothened (Smo) inhibitor13, blocked luciferase activation, consistent with Shh pathway inhibition, whereas C-2 had no effect.

Click to enlarge
Rating
Source Br J Cancer 2014 111(6), 1168-79. LDE225 (NVP-LDE225,Erismodegib) purchased from Selleck
Method Western blot
Cell Lines 786-O, 786-P, 786-O SuR cells
Concentrations 0-5 uM
Incubation Time 24 h
Results Western blot revealed that NVP-LDE225 at a concentration of 5 mM not only moderately reduced Gli-1 expression by B60%, but also moderately inhibited the activity of two well-known transducers of cell proliferation and survival, Akt and MAPK, by B40%. Moreover, Gli-2 expression decreased by NVP-LDE225 in a concentration-dependent manner.

Click to enlarge
Rating
Source Br J Cancer 2014 111(6), 1168-79. LDE225 (NVP-LDE225,Erismodegib) purchased from Selleck
Method Immunofluorescent staining
Cell Lines 786-O SuR cells
Concentrations 2.5 uM
Incubation Time 24 h
Results Actin cytoskeleton organisation of 786-O SuR cells was analysed by confocal microscopy. Actin-based structures were revealed by phalloidin, whereas localisation of focal adhesion points was achieved by fluorescent staining of p-paxillin. b-actin and p-paxillin were well organised in untreated cells; instead, NVP-LDE225 were able to mildly disassemble cytoskeleton organisation and focal adhesion points formation. These effects were much more evident with the combination NVP-LDE225 with sunitinib.

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.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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