Home
Resources
Publications
Discovery, Molecular and Pharmacological Characterization of GSA-10, a Novel Small-Molecule Positive Modulator of Smoothened

Discovery, Molecular and Pharmacological Characterization of GSA-10, a Novel Small-Molecule Positive Modulator of Smoothened

Tatiana Gorojankina, Lucile Hoch, Hélène Faure, Hermine Roudaut, Elisabeth Traiffort, Angèle Schoenfelder, Nicolas Girard, André Mann, Fabrizio Manetti, Antonio Solinas, Elena Petricci, Maurizio Taddei, etc.

Mol Pharmacol. 2013 May;83(5):1020-9.

PMID: 23448715

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP300833958	GSA-10		300833-95-8	Price
AP334998366	CUR61414		334998-36-6	Price

As a specialist in analytical chemical Products, Alfa Chemistry offers consumers a wealth of raw materials and a full range of technologies and services.

QUICK LINKS

HEADQUARTERS

Tel:

Fax:

Email: