Smoothened (Smo) is a transmembrane protein that serves as a key activator of the hedgehod (Hh) signaling pathway. LDE225 is a potent and selective Smo antagonist with IC50 values of 1.3 and 2.5nM for mouse and human, respectively[6]. It is tightly bound to human, mouse, and rat plasma proteins (99%), but moderately bound to monkey (85%) and dog (77%) plasma proteins.
The combination of LDE225 (20μM) and nilotinib (2μM) more efficiently inhibited the outgrowth of BaF3 cells expressing wt-BCRABL and BCR-ABL mutants as compared to cells treated with either agent alone[4]. In the mouse subcutaneous Ptch+/-p53-/- medulloblastoma allograft model, daily oral administration of LDE225 diphosphate salt (5, 10, or 20mg/kg/day) for 13 days significantly inhibited tumor growth with T/C values of 33%, 51%, and 83%, respectively, as compared to vehicle-treated controls. A single oral dose of LDE225 diphosphate salt (5, 10, or 20mg/kg/day) inhibited Gli1mRNA expression in the mouse medulloblastoma model at a dose- and time-dependent manner[5].
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