Molecule

Description

Cancer

Description

LDE225 (NVP-LDE225) is a smoothened antagonist with IC50 of 1.3 nM (mouse) and 2.5 nM (human), respectively.

Targets

IC₅₀

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 pK_a 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]

Clinical Trials

LDE225 has entered in a Phase II clinical trial in the treatment of basal cell carcinoma.

Features

Description

Compared with single agents, the combination of LDE225 and nilotinib is more effective at reducing the outgrowth of resistant cell clones. Also co-treatment with LDE225 and nilotinib results in significantly more inhibition of growth than treatment with either agent alone in BaF3 cells expressing wt-BCR-ABL and BCR-ABL mutants (M244V, G250E, Q252H, Y253F, E255K, T315A, T315I, F317L, F317V, M351T, H396P). LDE225 and nilotinib generates synergistic effect of simultaneous in BaF3 cells expressing T315I. The LDE225 and nilotinib combination more effectively inhibits tumor growth in mice compared to either vehicle- or nilotinib- or LDE225-treated mice. ^[3] LDE-225 plus Gemcitabine has entered in a phase II clinical trial in the treatment of resectable pancreatic adenocarcinoma.

Cell Lines

TM3Hh12 cells

Concentrations

~10 μM

Incubation Time

30 minutes

Methods

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 package.

Animal Models

Orthotopic Ptch^+/-p53^-/- medulloblastoma allograft model in athymic nude mice

Formulation

0.5% sodium carboxymethyl cellulose

Doses

40 mg/kg/day

Administration

Administered via p.o. or b.i.d