LDE225 (NVP-LDE225,Erismodegib)

 

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

Biological Activity

Description	LDE225 (NVP-LDE225) is a Smoothened (Smo) antagonist, inhibiting Hedgehog (Hh) signaling with IC50 of 1.3 nM (mouse) and 2.5 nM (human), respectively. Phase 3.
Targets	Smo (mouse)	Smo (human)
IC50	1.3 nM	2.5 nM [1]
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]
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
Dosages	40 mg/kg/day
Administration	Administered via p.o. or b.i.d
Solubility	0.5% CMC, 15 mg/mL

1

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT01764776	Recruiting	Normal Hepatic Function,|Impaired Hepatic Function	Novartis|Novartis Pharmaceuticals	2013-03	Phase 1
NCT01769768	Recruiting	Advanced Solid Tumor	Novartis|Novartis Pharmaceuticals	2013-04	Phase 1
NCT01708174	Recruiting	Medulloblastoma	Novartis|Novartis Pharmaceuticals	2013-05	Phase 3
NCT01787552	Recruiting	Primary Myelofibrosis|Thrombocythemia, Essential|Thrombocytosis|Myeloproliferative Disorders|Bone Marrow Diseases|Hematologic Diseases|Blood Coagulation Disorders|Blood Platelet Disorders|Hemorrhagic Disorders	Novartis|Novartis Pharmaceuticals	2013-05	Phase 1|Phase 2
NCT01826214	Not yet recruiting	Acute Leukemias	Novartis|Novartis Pharmaceuticals	2013-05	Phase 2

Chemical Information

Download LDE225 (NVP-LDE225,Erismodegib) SDF

Chemical Name	[1,1’-Biphenyl]-3-carboxamide, N-[6-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-3-pyridinyl]-2-methyl-4’-(trifluoromethoxy)-, rel-

Preparing Stock Solutions

Stock Solution (1ml DMSO)	1mM	10mM	20mM	30mM
Mass(mg)	0.4855	4.855	9.71	14.565

Customer Reviews (1)

Click to enlarge	Rating
	Source	nature CHEMICAL BIOLOGY, 2013. 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.

Product Citations (2)

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  Inhibitors of Hedgehog acyltransferase block Sonic Hedgehog signaling. [Petrova E, et al. Nat Chem Biol 2013;9(4):247-9]

  
  


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  Inhibitors of Hedgehog acyltransferase block Sonic Hedgehog signaling. [Petrova E Nat Chem Biol 2013;9(4):247-9]