LY2940680

LY2940680 (Taladegib) is potent Smoothened (SMO) receptor antagonist, potently inhibits Hedgehog (Hh) signaling with IC50 of 6.3 nM in Gli-luc reporter assyas; inhibits medulloblastoma cell proliferation isolated from Ptch+/–p53–/– mice with IC50 of 43.5 nM; demonstrates anti-tumor activity in vivo with advanced basal cell carcinoma (BCC) and other malignancies.Ovarian Cancer Phase 2 Clinical (In Vitro) :Taladegib, a small-molecule antagonist of the smoothened receptor, shows a slight inhibitory effect on cell proliferation without differences between mucin- (IC50: Taladegib=49.8±4.5 μM) and mixed- Cholangiocarcinoma (CCA) (IC50: Taladegib=61.2±21.1 μM) . The IC50 for Taladegib inhibition of [3H]MRT-92 binding is right shifted (3- to 100-fold) for the S387AECL2, L325F3.36f, and D473H6.54f mutants but did not differ from that of WT receptor for the other mutants. The ability of SANT-1 to inhibit [3H]MRT-92 binding to V329F3.40f and T466F6.47f mutants is abolished, and it is severely impaired for L325F3.40f, I408F5.51f, and M525G7.45f mutants (4- to 140-fold drop of the IC50), but is not modified for the S387AECL2 mutant. Taken together, these data confirm our docking hypothesis that MRT-92-binding mode differs from that of either Taladegib or SANT-1 by simultaneously occupying binding sites 1 and 2.