Sonidegib diphosphate (LDE225 diphosphate) is an effective and selective Smo antagonist (IC50: 1.3 nM and 2.5 nM for mouse and human Smo in a binding assay, respectively).

Erismodegib diphosphate, a small molecule, clinically investigated SMO inhibitor. Erismodegib diphosphate is 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). In a similar fashion to cyclopamine, Erismodegib interacts directly with SMO, to reduce the expression of downstream Hh signaling targets. The IC50 values for Erismodegib diphosphate for the major human CYP450 drug-metabolizing enzymes are greater than 10 μM. 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 obviously downregulated following exposure to Erismodegib (10 nM; 0.78-fold and 100 nM; 0.73-fold, respectively (p<0.01)[2].

Erismodegib diphosphate is a weak base with a measured pKa of 4.2 and exhibits relatively poor aqueous solubility. Erismodegib diphosphate demonstrates dose-related antitumor activity after 10 days of oral administration of a suspension of the diphosphate salt, in the subcutaneous Ptch+/-p53-/- medulloblastoma allograft mouse model. Bone marrow cells and spleen cells from a subset of treated mice are transplanted into secondary recipient mice. Erismodegib diphosphate (5 mg/kg/day; once daily) obviously inhibits tumor growth, corresponding to a T/C value of 33% (p<0.05 as compared to vehicle controls). Erismodegib affords 51 and 83% regression respectively when dosed at 10 and 20 mg/kg/day qd [1]. Transplantation of either bone marrow (BM) or spleen cells from mice treated with Erismodegib diphosphate+ Nilotinib results in reduced white cell count (WCC) and reduces leukaemia development in secondary recipients compared to Erismodegib or Nilotinib alone[2].