Abstract
The seven-transmembrane receptor Smoothened (Smo) is the major component involved in signal transduction of the Hedgehog (Hh) morphogens. Smo inhibitors represent a promising alternative for the treatment of several types of cancers linked to abnormal Hh signalling. Here, based on experimental data, we generated and validated a pharmacophoric model for Smo inhibitors constituted by three hydrogen bond acceptor groups and three hydrophobic regions. We used this model for the virtual screening of a library of commercially available compounds. Visual and structural criteria allowed the selection of twenty top scoring ligands and an acylthiourea, MRT-10 was identified and characterized as a Smo antagonist. The corresponding acylurea MRT-14 was synthesized and shown to display, in various Hh assays, an inhibitory potency comparable or greater to that of Cyclopamine and Cur61414, reference Smo antagonists. Focused virtual screening of the same library further identified five additional related antagonists. MRT-10 and MRT-14 constitute the first members of novel families of Smo antagonists. The described virtual screening approach is aimed at identifying novel modulators of Smo and of other G-protein coupled receptors
Footnotes
- The American Society for Pharmacology and Experimental Therapeutics