Sonidegib (LDE-225)


Catalog No. size PriceQuantity
M7110-2 2mg solid $121
M7110-10 10mg solid $482

Description

Cas:956697-53-3 (free base)

Product Information

Sonidegib, also known as, erismodegib, LDE225, NVP-LDE225, is an orally bioavailable small-molecule Smoothened (Smo) antagonist with potential antineoplastic activity. Erismodegib selectively binds to the Hedgehog (Hh)-ligand cell surface receptor Smo, which may result in the suppression of the Hh signaling pathway and, so, the inhibition of tumor cells in which this pathway is abnormally activated. It was approved by the FDA for treating basal cell carcinoma in July 2015.

 

Chemical Formula: C26H26F3N3O3

 

Exact Mass: 485.19263

 

Molecular Weight: 485.49815

 

Elemental Analysis: C, 64.32; H, 5.40; F, 11.74; N, 8.66; O, 9.89

 

Synonym: 

 

LDE225

LDE 225

LDE-225

NVP-LDE225

NVP-LDE-225

NVP LDE225

Erismodegib

Sonidegib

Odomzo

 

Chemical Name: N-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide

 

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+

 

Smiles Code:

O=C(C1=C(C)C(C2=CC=C(OC(F)(F)F)C=C2)=CC=C1)NC3=CC=C(N4C[C@@H](C)O[C@@H](C)C4)N=C3

 

 

Technical Data:

 

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

 

In Vitro

The IC50 values for Sonidegib (NVP-LDE225) for the major human CYP450 drug metabolizing enzymes is greater than 10 μM. Sonidegib (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). Sonidegib 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)±Sonidegib 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 Sonidegib (10 nM; 0.78-fold and 100 nM; 0.73-fold, respectively (p<0.01).

 

In Vivo

Sonidegib (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, Sonidegib 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, Sonidegib 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, Sonidegib affords 51 and 83% regression, respectively. 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 Sonidegib (LDE225)+Nilotinib results in reduced white cell count (WCC) and reduces leukaemia development in secondary recipients compared to Sonidegib or Nilotinib alone.

 

 

References

 

  1. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Available from http://www.ncbi.nlm.nih.gov/books/NBK548922/ PubMed PMID: 31644228.

 

  1. Li Y, Song Q, Day BW. Phase I and phase II sonidegib and vismodegib clinical trials for the treatment of paediatric and adult MB patients: a systemic review and meta-analysis. Acta Neuropathol Commun. 2019 Jul 30;7(1):123. doi: 10.1186/s40478-019-0773-8. Review. PubMed PMID: 31362788; PubMed Central PMCID: PMC6668073.

 

  1. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006-. Available from http://www.ncbi.nlm.nih.gov/books/NBK500869/ PubMed PMID: 29999928.

 

  1. Sonidegib for basal cell carcinoma. Aust Prescr. 2018 Jun;41(3):94. doi: 10.18773/austprescr.2018.025. Epub 2018 May 15. Review. PubMed PMID: 29922006; PubMed Central PMCID: PMC6003011.

 

  1. Jain S, Song R, Xie J. Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas. Onco Targets Ther. 2017 Mar 16;10:1645-1653. doi: 10.2147/OTT.S130910. eCollection 2017. Review. PubMed PMID: 28352196; PubMed Central PMCID: PMC5360396.

 

  1. Wahid M, Jawed A, Dar SA, Mandal RK, Haque S. Differential pharmacology and clinical utility of sonidegib in advanced basal cell carcinoma. Onco Targets Ther. 2017 Jan 24;10:515-520. doi: 10.2147/OTT.S97713. eCollection 2017. Review. PubMed PMID: 28182134; PubMed Central PMCID: PMC5279825.

 

Products are for research use only. Not for human use.

 

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