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1218778-77-8

1218778-77-8 structure
1218778-77-8 structure
  • Name: LDE225 (Diphosphate)
  • Chemical Name: N-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide,phosphoric acid
  • CAS Number: 1218778-77-8
  • Molecular Formula: C26H32F3N3O11P2
  • Molecular Weight: 681.489
  • Catalog: Signaling Pathways Stem Cell/Wnt Smo
  • Create Date: 2016-12-13 23:02:40
  • Modify Date: 2024-01-02 18:59:49
  • Erismodegib diphosphate (LDE225 diphosphate) is a potent and selective Smo antagonist with IC50 of 1.3 nM and 2.5 nM for mouse and human Smo in binding assay, respectively.

Name N-[6-[(2S,6R)-2,6-dimethylmorpholin-4-yl]pyridin-3-yl]-2-methyl-3-[4-(trifluoromethoxy)phenyl]benzamide,phosphoric acid
Synonyms [1,1'-Biphenyl]-3-carboxamide, N-[6-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-3-pyridinyl]-2-methyl-4'-(trifluoromethoxy)-, phosphate (1:2)
LDE225 Diphosphate
LDE-225 Diphosphate
N-{6-[(2R,6S)-2,6-Dimethyl-4-morpholinyl]-3-pyridinyl}-2-methyl-4'-(trifluoromethoxy)-3-biphenylcarboxamide phosphate (1:2)
Sonidegib phosphate
LDE 225 Diphosphate
UNII:W421AI34UW
Odomzo
Erismodegib Diphosphate
UNII-W421AI34UW
NVP-LDE 225 Diphosphate
CS-1175
LDE225 (Diphosphate)
Description Erismodegib diphosphate (LDE225 diphosphate) is a potent and selective Smo antagonist with IC50 of 1.3 nM and 2.5 nM for mouse and human Smo in binding assay, respectively.
Related Catalog
Target

IC50: 1.3 nM (mSmo), 2.5 nM (hSmo)[1]

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].
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 (LDE225)+ Nilotinib results in reduced white cell count (WCC) and reduces leukaemia development in secondary recipients compared to Erismodegib or Nilotinib alone[2].
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.
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.
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.

[3]. Ma W, et al. Reduced Smoothened level rescued Aβ-induced memory deficits and neuronal inflammation in animal models of Alzheimer's disease. J Genet Genomics. 2018 May 20;45(5):237-246.

Molecular Formula C26H32F3N3O11P2
Molecular Weight 681.489
Exact Mass 681.146423
PSA 242.32000
LogP 4.41330
Storage condition 2-8℃