Erismodegib diphosphate (Sonidegib 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. IC50 & Target: IC50: 1.3 nM (mSmo), 2.5 nM (hSmo)^[1] In Vitro: The IC₅₀ values for Erismodegib diphosphate (Sonidegib diphosphate) for the major human CYP450 drug metabolizing enzymes is greater than 10 μM^[1]. Erismodegib diphosphate, 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 diphosphate (Sonidegib diphosphate) is a weak base with a measured pK_a of 4.2 and exhibits relatively poor aqueous solubility. In the subcutaneous Ptch^+/-p53^-/- medulloblastoma allograft mouse model, Erismodegib diphosphate 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 diphosphate 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 diphosphate+ Nilotinib results in reduced white cell count (WCC) and reduces leukaemia development in secondary recipients compared to Erismodegib or Nilotinib alone^[2].