LDE225

LDE225 (NVP-LDE225; Erismodegib) is a Smoothened (Smo) antagonist, inhibiting Hedgehog (Hh) signaling with IC50 of 1.3 nM (mouse) and 2.5 nM (human), respectively. (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.

956697-53-3

NVP-LDE225, Erismodegib

>98% (HPLC)

Ethanol: 97 mg/mL (199.79 mM) ; DMSO: 97 mg/mL (199.79 mM)

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

C26H26F3N3O3

485.5

Storage temperature: -20°C. Stability: ≥ 2 years