Introduction：Basic information about CAS 956697-53-3|LDE225 (NVP-LDE225,Erismodegib), including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
| Common Name | LDE225 (NVP-LDE225,Erismodegib) |
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| CAS Number | 956697-53-3 | Molecular Weight | 485.498 |
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| Density | 1.3±0.1 g/cm3 | Boiling Point | 544.5±50.0 °C at 760 mmHg |
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| Molecular Formula | C26H26F3N3O3 | Melting Point | / |
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| MSDS | / | Flash Point | 283.1±30.1 °C |
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Names
| Name | Erismodegib |
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| Synonym | More Synonyms |
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LDE225 (NVP-LDE225,Erismodegib) BiologicalActivity
| Description | Erismodegib (LDE225) is a potent and selective Smoothened (Smo) antagonist with IC50s of 1.3 nM and 2.5 nM for mouse and human Smo, respectively. |
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| Related Catalog | Signaling Pathways >>Stem Cell/Wnt >>SmoResearch Areas >>Cancer |
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| Target | IC50: 1.3 nM (mSmo), 2.5 nM (hSmo)[1] |
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| In Vitro | The IC50 values for Erismodegib (NVP-LDE225) for the major human CYP450 drug metabolizing enzymes is greater than 10 μM[1]. Erismodegib (LDE225), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with Nilotinib, inhibits the Hh pathway in CD34+ chronic phase (CP)-chronic myeloid leukaemia (CML) cells, reducing the number and self-renewal capacity of CML leukaemia stem cell (LSC). Erismodegib interacts directly with SMO, in a similar fashion to cyclopamine, to reduce expression of downstream Hh signaling targets. Primary CD34+ CP-CML cells are cultured in serum free media (SFM)±Erismodegib for 6, 24 and 72 hours (h). At 72 h, while there is variability between the biological samples, GLI1 is significantly downregulated following exposure to Erismodegib (10 nM; 0.78-fold and 100 nM; 0.73-fold, respectively (p<0.01)[2]. |
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| In Vivo | Erismodegib (NVP-LDE225) is a weak base with a measured pKa of 4.2 and exhibits relatively poor aqueous solubility. In the subcutaneous Ptch+/-p53-/- medulloblastoma allograft mouse model, Erismodegib demonstrates dose-related antitumor activity after 10 days of oral administration of a suspension of the diphosphate salt. At a dose of 5 mg/kg/day qd, Erismodegib significantly inhibits tumor growth, corresponding to a T/C value of 33% (p<0.05 as compared to vehicle controls). When dosed at 10 and 20 mg/kg/day qd, Erismodegib affords 51 and 83% regression, respectively[1]. Bone marrow cells and spleen cells from a subset of treated mice are transplanted into secondary recipient mice. Transplantation of either bone marrow (BM) or spleen cells from mice treated with Erismodegib+Nilotinib results in reduced white cell count (WCC) and reduces leukaemia development in secondary recipients compared to Erismodegib or Nilotinib alone[2]. |
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| Cell Assay | CD34+ CP-CML cells are seeded in SFM alone ±Erismodegib± Nilotinib and cultured for 24-72 h prior to assessment. Proliferation is measured using colorimetric assessment of BrDU incorporation. Proportion of viable cells versus those in early and late apoptosis is assessed by flow cytometry using annexin V-FITC and 7-amino-actinomycin D (7-AAD, Via-Probe solution). Cell cycle status is assessed using Ki67 (FITC) expression and 7-AAD incorporation[2]. |
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| Animal Admin | Mice[2] The transgenic EGFP+/SCLtTA/TRE-BCR-ABL mouse model is used to investigate the effect of Erismodegib treatment on CML LSC in vivo. Scl-tTa-BCR-ABL mice in the FVB/N background are crossed with transgenic GFP-expressing mice. Bone marrow cells are obtained 4 weeks post induction, GFP+ cells are selected by flow cytometry and transplanted by tail vein injection (106 cells/mouse) into wild-type FVB/N recipient mice, irradiated at 900 cGy, generating a large cohort of mice with similar time of onset of leukemia. Blood samples obtained 4 weeks post transplantation confirmed a neutrophilic leukocytosis in recipient mice. Mice are treated with Nilotinib (50 mg/kg by gavage, daily), Erismodegib (80 mg/kg by gavage, daily), Erismodegib+ Nilotinib, or with vehicle alone (control). After 3 weeks of treatment, animals are euthanised and marrow content of femurs and tibiae, spleen cells and blood obtained. Total white cell count (WCC), GFP-expressing WCC, myeloid cells, and GFP+ progenitors and stem cells are measured by flow cytometry. Survival is assessed in a subset of mice for 120d post discontinuation of treatment. Spleen and BM cells from a subset of mice in each arm are pooled and 5×106 cells/mouse (8 mice/condition) are transplanted into wild-type FVB/N recipient mice irradiated at 900 cGy. Engraftment is monitored by drawing peripheral blood (PB) every 4 weeks. The percentage of GFP+ cells in PB is analyzed by flow cytometry. |
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| References | [1]. Pan S, et al. Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist. ACS Med Chem Lett. 2010 Mar 16;1(3):130-4. [2]. Irvine DA, et al. 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. |
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Chemical & Physical Properties
| Density | 1.3±0.1 g/cm3 |
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| Boiling Point | 544.5±50.0 °C at 760 mmHg |
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| Molecular Formula | C26H26F3N3O3 |
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| Molecular Weight | 485.498 |
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| Flash Point | 283.1±30.1 °C |
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| Exact Mass | 485.192627 |
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| PSA | 63.69000 |
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| LogP | 5.43 |
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| Vapour Pressure | 0.0±1.5 mmHg at 25°C |
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| Index of Refraction | 1.569 |
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| InChIKey | VZZJRYRQSPEMTK-CALCHBBNSA-N |
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| SMILES | Cc1c(C(=O)Nc2ccc(N3CC(C)OC(C)C3)nc2)cccc1-c1ccc(OC(F)(F)F)cc1 |
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| Storage condition | -20°C |
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Synonyms
| N-{6-[(2R,6S)-2,6-Dimethyl-4-morpholinyl]-3-pyridinyl}-2-methyl-4'-(trifluoromethoxy)-3-biphenylcarboxamide |
| LDE225 (NVP-LDE225, Erismodegib) |
| [1,1'-Biphenyl]-3-carboxamide, N-[6-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-3-pyridinyl]-2-methyl-4'-(trifluoromethoxy)- |
| Erismodegib |
| Sonidegib |
| LDE225 |
| UNII:0RLU3VTK5M |
| LDE225(NVP-LDE225) Erismodegib |
| LDE 225 |
| NVP-LDE225 |
