LDE225 (NVP-LDE225, Erismodegib)

Alias: Sonidegib; LDE 225; NVP-LDE225; LDE-225; NVP LDE-225; LDE225; NVP LDE225; Erismodegib; trade name of Odomzo
Cat No.:V1333 Purity: ≥98%
Erismodegib (formerly LDE-225; NVP LDE-225; LDE225; NVP-LDE22; Sonidegib; trade name of Odomzo) is an orally bioavailable small-molecule antagonist of the Smoothened (Smo) in Hedgehog signaling pathway with potential antitumor activity.
LDE225 (NVP-LDE225, Erismodegib) Chemical Structure CAS No.: 956697-53-3
Product category: Hedgehog(Smoothened) ROCK
This product is for research use only, not for human use. We do not sell to patients.
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25mg
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Other Forms of LDE225 (NVP-LDE225, Erismodegib):

  • Sonidegib phosphate (NVP-LDE-225, Erismodegib, Odomzo)
Official Supplier of:
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Erismodegib (formerly LDE-225; NVP LDE-225; LDE225; NVP-LDE22; Sonidegib; trade name of Odomzo) is an orally bioavailable small-molecule antagonist of the Smoothened (Smo) in Hedgehog signaling pathway with potential antitumor activity. It suppresses Hedgehog (Hh) signaling with an IC50 of 1.3 nM for mice and 2.5 nM for humans in cell-free assays. LDE225 (NVP-LDE225, Erismodegib, Sonidegib), an anticancer drug that has been approved, binds specifically to the cell surface receptor Smo that carries the Hedgehog (Hh) ligand. This suppresses the Hedgehog signaling pathway, which restricts the growth of tumor cells that have an aberrantly activated Hedgehog pathway. For the treatment of basal cell carcinoma, the FDA approved this anticancer medication in 2015.

Biological Activity I Assay Protocols (From Reference)
Targets
mSmo ( IC50 = 1.3 nM ); hSmo ( IC50 = 2.5 nM )
ln Vitro

In vitro activity: Sonidegib (NVP-LDE225) has an IC50 value of more than 10 μM for the main human CYP450 drug-metabolizing enzymes[1]. When used alone or in conjunction with nilotinib, sonidegib (LDE225), a small molecule SMO inhibitor under clinical investigation, inhibits the Hh pathway in CD34+ chronic phase (CP)-chronic myeloid leukemia (CML) cells, thereby decreasing the quantity and potential for self-renewal of CML leukaemia stem cells (LSC). Similar to cyclopamine, sonidegib directly interacts with SMO to decrease the expression of downstream Hh signaling targets. Serum-free medium (SFM)±Sonidegib is used to cultivate primary CD34+ CP-CML cells for 6, 24, and 72 hours (h). After being exposed to Sonidegib at 10 nM; 0.78-fold and 100 nM; 0.73-fold, respectively (p<0.01), GLI1 is significantly downregulated at 72 hours, although there is variability amongst the biological samples[2].

ln Vivo
Sonidegib (NVP-LDE225) has a pKa of 4.2, making it a weak base with comparatively low solubility in water. Sonidegib exhibits dose-related antitumor activity in the subcutaneous Ptch+/-p53-/- medulloblastoma allograft mouse model following ten days of oral administration of a suspension of the diphosphate salt. Sonidegib exhibits a significant tumor growth inhibition at a dose of 5 mg/kg/day qd, with a corresponding T/C value of 33% (p<0.05) in comparison to vehicle controls. Sonidegib provides 51 and 83% regression when administered at doses of 10 and 20 mg/kg/day qd, respectively[1]. Secondary recipient mice are transplanted with bone marrow and spleen cells from a subset of treated mice. In comparison to Sonidegib or Nilotinib alone, transplanting bone marrow (BM) or spleen cells from mice treated with Sonidegib (LDE225)+Nilotinib reduces leukaemia development and the number of white blood cells (WCC) in secondary recipients[2].
Enzyme Assay
LLDE225 blocks the TM3 luciferized cell line with 0.6 nM and 8 nM of Hh agonist Ag1.5 present, respectively.
Cell Assay
Prior to assessment, CD34+ CP-CML cells are cultured for 24-72 hours in SFM alone±Sonidegib±Nilotinib. BrDU incorporation colorimetric assessment is used to quantify proliferation. Utilizing annexin V-FITC and 7-amino-actinomycin D (7-AAD, Via-Probe solution), flow cytometry is used to determine the ratio of viable cells to those in early and late apoptosis. Ki67 (FITC) expression and 7-AAD incorporation are used to determine the cell cycle status.
Animal Protocol
Mice: The impact of sonidegib treatment on CML LSC is examined in vivo using the transgenic EGFP+/SCLtTA/TRE-BCR-ABL mouse model. Transgenic GFP-expressing mice are crossed with Scl-tTa-BCR-ABL mice in the FVB/N background. After 4 weeks of induction, bone marrow cells are extracted. GFP+ cells are then identified using flow cytometry and injected into the tail veins of wild-type FVB/N recipient mice at a density of 106 cells per mouse. The mice are then exposed to 900 cGy of radiation, creating a sizable cohort of mice with similar leukemia onset times. The recipient mice's neutrophilic leukocytosis was confirmed by blood samples taken four weeks after transplantation. Nilotinib (50 mg/kg by gavage, daily), Sonidegib (80 mg/kg by gavage, daily), Sonidegib + Nilotinib, or vehicle alone (control) are the treatment options given to mice. The animals are put to sleep after three weeks of treatment, and blood, spleen cells, and the contents of the femur and tibiae's marrow are extracted. Using flow cytometry, the total white cell count (WCC), GFP-expressing WCC, myeloid cells, and GFP+ progenitors and stem cells are quantified. A subgroup of mice is evaluated for survival 120 days after treatment termination. After combining sperm and bone marrow cells from a subgroup of mice in each arm, 5x106 cells/mouse (eight mice per condition) are injected into wild-type FVB/N recipient mice that have been exposed to 900 cGy of radiation. Peripheral blood (PB) is drawn every four weeks to monitor engraftment. Flow cytometry is used to determine the proportion of GFP+ cells in PB.
References

[1]. Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist. ACS Med Chem Lett. 2010 Mar 16;1(3):130-4.

[2]. Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia. Sci Rep. 2016 May 9;6:25476.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C26H26F3N3O3
Molecular Weight
485.5
Exact Mass
485.19
Elemental Analysis
C, 64.32; H, 5.40; F, 11.74; N, 8.66; O, 9.89
CAS #
956697-53-3
Appearance
Solid powder
SMILES
C[C@@H]1CN(C[C@@H](O1)C)C2=NC=C(C=C2)NC(=O)C3=CC=CC(=C3C)C4=CC=C(C=C4)OC(F)(F)F
InChi Key
VZZJRYRQSPEMTK-CALCHBBNSA-N
InChi Code
InChI=1S/C26H26F3N3O3/c1-16-14-32(15-17(2)34-16)24-12-9-20(13-30-24)31-25(33)23-6-4-5-22(18(23)3)19-7-10-21(11-8-19)35-26(27,28)29/h4-13,16-17H,14-15H2,1-3H3,(H,31,33)/t16-,17+
Chemical Name
N-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide
Synonyms
Sonidegib; LDE 225; NVP-LDE225; LDE-225; NVP LDE-225; LDE225; NVP LDE225; Erismodegib; trade name of Odomzo
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: 50~97 mg/mL (103~199.8 mM)
Water: <1 mg/mL
Ethanol: ~97 mg/mL (~199.8 mM)
Solubility (In Vivo)
2% DMSO+corn oil: 10 mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.0597 mL 10.2987 mL 20.5973 mL
5 mM 0.4119 mL 2.0597 mL 4.1195 mL
10 mM 0.2060 mL 1.0299 mL 2.0597 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT02111187 Completed Drug: LDE225 Prostate Cancer Sidney Kimmel Comprehensive
Cancer Center at Johns
Hopkins
April 2014 Phase 1
NCT02195973 Completed Drug: LDE225 Recurrent Ovarian Cancer University of Alabama at Birmingham September 2014 Phase 1
NCT01764776 Completed Drug: LDE225 Normal Hepatic Function
Impaired Hepatic Function
Novartis Pharmaceuticals March 2013 Phase 1
NCT02138929 Completed Drug: Everolimus
Drug: LDE 225
Esophageal Cancer M.D. Anderson Cancer Center November 10, 2014 Phase 1
NCT01954355 Completed Drug: LDE225
Drug: Paclitaxel
Solid Tumor
Ovarian Cancer
Swiss Group for Clinical Cancer
Research
September 2013 Phase 1
Biological Data
  • LDE225 (Sonidegib)

    Antitumor activity in an orthotopic Ptch+/−p53−/−medulloblastoma allograft model in nude mice upon treatment with5mdiphosphate salt dosed at 40 mg/kg/day po bid or vehicle at equal dose volume.. 2010 Jun 10; 1(3): 130–134.

  • LDE225 (Sonidegib)

    Antitumor activity upon treatment with5mdiphosphate salt or vehicle in a Ptch+/−p53−/− medulloblastoma subcutaneous allograft model in nude mice.. 2010 Jun 10; 1(3): 130–134.

  • LDE225 (Sonidegib)

    Gli1 mRNA inhibition (open circle), tumor PK (filled squares), and plasma PK (filled triangles) in Ptch+/−p53−/−medulloblastoma model after treatment with5m (Sonidegib, or erismodegib, LDE225, NVP-LDE225).. 2010 Jun 10; 1(3): 130–134.

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