A new smoothened antagonist bearing the purine scaffold shows antitumour activity in vitro and in vivo
Author
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Zarate, Ana María
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Espinosa Bustos, Christian
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Guerrero, Simón
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Fierro, Angélica
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Oyarzún Ampuero, Felipe
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Geoffery Quest, Andrew
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Di Marcotullio, Lucía
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Loricchio, Elena
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Caimano, Miriam
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Calcaterra, Andrea
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González Quiroz, Matías
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Aguirre, Adam
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Meléndez, Jaime
Author
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Salas, Cristian O.
Admission date
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2021-12-10T15:27:54Z
Available date
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2021-12-10T15:27:54Z
Publication date
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2021
Cita de ítem
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Int. J. Mol. Sci. 2021, 22, 8372
es_ES
Identifier
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10.3390/ijms22168372
Identifier
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https://repositorio.uchile.cl/handle/2250/183147
Abstract
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The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, synthesised, and biologically tested to provide an insight to their mechanism of action. Compound 4s was the most active and the best inhibitor of cell growth and selectively cytotoxic to cancer cells. 4s induced cell cycle arrest, apoptosis, a reduction in colony formation and downregulation of PTCH and GLI1 expression. BODIPY-cyclopamine displacement assays confirmed 4s is a SMO antagonist. In vivo, 4s strongly inhibited tumour relapse and metastasis of melanoma cells in mice. In vitro, 4s was more efficient than vismodegib to induce apoptosis in human cancer cells and that might be attributed to its dual ability to function as a SMO antagonist and apoptosis inducer.
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Patrocinador
dc.description.sponsorship
FONDECYT Program from the Chilean Government
CONICYT Program from the Chilean Government
FONDAP Program from the Chilean Government
FONDEQUIP Program from the Chilean Government
Fondazione AIRC per la ricerca sul cancro IG20801
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Lenguage
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en
es_ES
Publisher
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MDPI
es_ES
Type of license
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Attribution-NonCommercial-NoDerivs 3.0 United States