Taladegib

Taladegib (LY2940680) is an antagonist of the smoothened receptor. IC50 & Target: Smo^[1] 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)^[1]. The IC₅₀ for Taladegib inhibition of [³H]MRT-92 binding is right shifted (3- to 100-fold) for the S387A^ECL2, L325F^3.36f, and D473H^6.54f 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 V329F^3.40f and T466F^6.47f mutants is abolished, and it is severely impaired for L325F^3.40f, I408F^5.51f, and M525G^7.45f mutants (4- to 140-fold drop of the IC₅₀), but is not modified for the S387A^ECL2 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^[2].