RT Journal Article
SR Electronic
T1 Discovery, Molecular and Pharmacological Characterization of GSA-10, a Novel Small-Molecule Positive Modulator of Smoothened
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1020
OP 1029
DO 10.1124/mol.112.084590
VO 83
IS 5
A1 Gorojankina, Tatiana
A1 Hoch, Lucile
A1 Faure, Hélène
A1 Roudaut, Hermine
A1 Traiffort, Elisabeth
A1 Schoenfelder, Angèle
A1 Girard, Nicolas
A1 Mann, André
A1 Manetti, Fabrizio
A1 Solinas, Antonio
A1 Petricci, Elena
A1 Taddei, Maurizio
A1 Ruat, Martial
YR 2013
UL http://molpharm.aspetjournals.org/content/83/5/1020.abstract
AB Activation of the Smoothened (Smo) receptor mediates Hedgehog (Hh) signaling. Hh inhibitors are in clinical trials for cancer, and small-molecule Smo agonists may have therapeutic interests in regenerative medicine. Here, we have generated and validated a pharmacophoric model for Smo agonists and used this model for the virtual screening of a library of commercially available compounds. Among the 20 top-scoring ligands, we have identified and characterized a novel quinolinecarboxamide derivative, propyl 4-(1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido) benzoate, (GSA-10), as a Smo agonist. GSA-10 fits to the agonist pharmacophoric model with two hydrogen bond acceptor groups and four hydrophobic regions. Using pharmacological, biochemical, and molecular approaches, we provide compelling evidence that GSA-10 acts at Smo to promote the differentiation of multipotent mesenchymal progenitor cells into osteoblasts. However, this molecule does not display the hallmarks of reference Smo agonists. Remarkably, GSA-10 does not recognize the classic bodipy-cyclopamine binding site. Its effect on cell differentiation is inhibited by Smo antagonists, such as MRT-83, SANT-1, LDE225, and M25 in the nanomolar range, by GDC-0449 in the micromolar range, but not by cyclopamine and CUR61414. Thus, GSA-10 allows the pharmacological characterization of a novel Smo active site, which is notably not targeted to the primary cilium and strongly potentiated by forskolin and cholera toxin. GSA-10 belongs to a new class of Smo agonists and will be helpful for dissecting Hh mechanism of action, with important implications in physiology and in therapy.