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Title: Discovery, Molecular and Pharmacological Characterizationof GSA-10, a Novel Small-Molecule Positive Modulatorof Smoothened
Authors: Gorojankina, T
Hoch, L
Faure, H
Roudaut, H
Traiffort, E
Schoenfelder, A
Girard, N
Mann, A
Manetti, Fabrizio 
Solinas, A
Petricci, Elena 
Taddei, Maurizio 
Ruat, M.
Issue Date: 2013
Project: None 
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 interestsin regenerative medicine. Here, we have generated andvalidated a pharmacophoric model for Smo agonists and usedthis model for the virtual screening of a library of commerciallyavailable compounds. Among the 20 top-scoring ligands, wehave identified and characterized a novel quinolinecarboxamidederivative, 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 twohydrogen 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 progenitorcells into osteoblasts. However, this molecule does notdisplay the hallmarks of reference Smo agonists. Remarkably,GSA-10 does not recognize the classic bodipy-cyclopaminebinding site. Its effect on cell differentiation is inhibited by Smoantagonists, such as MRT-83, SANT-1, LDE225, and M25 in thenanomolar range, by GDC-0449 in the micromolar range, butnot by cyclopamine and CUR61414. Thus, GSA-10 allows thepharmacological characterization of a novel Smo active site,which is notably not targeted to the primary cilium and stronglypotentiated by forskolin and cholera toxin. GSA-10 belongs toa new class of Smo agonists and will be helpful for dissecting Hhmechanism of action, with important implications in physiologyand in therapy.
ISSN: 0026-895X
DOI: 10.1124/mol.112.084590
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