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Discovery, molecular and pharmacological characterization of GSA-10, a novel small-molecule positive modulator of Smoothened.

Abstract : 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.
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https://hal.archives-ouvertes.fr/hal-00851060
Contributor : Alain Perignon <>
Submitted on : Monday, August 12, 2013 - 10:32:11 AM
Last modification on : Wednesday, September 9, 2020 - 3:00:55 AM

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Tatiana Gorojankina, Lucile Hoch, Hélène Faure, Hermine Roudaut, Elisabeth Traiffort, et al.. Discovery, molecular and pharmacological characterization of GSA-10, a novel small-molecule positive modulator of Smoothened.. Molecular Pharmacology, American Society for Pharmacology and Experimental Therapeutics, 2013, 83 (5), pp.1020-9. ⟨10.1124/mol.112.084590⟩. ⟨hal-00851060⟩

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