Chemical, computational and functional insights into the chemical stability of the Hedgehog pathway inhibitor GANT61

Autor: Andrea Calcaterra, Valentina Iovine, Bruno Botta, Deborah Quaglio, Ilaria D’Acquarica, Alessia Ciogli, Antonia Iazzetti, Romina Alfonsi, Ludovica Lospinoso Severini, Paola Infante, Lucia Di Marcotullio, Mattia Mori, Francesca Ghirga
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 33, Iss 1, Pp 349-358 (2018)
Druh dokumentu: article
ISSN: 1475-6366
1475-6374
14756366
01013017
DOI: 10.1080/14756366.2017.1419221
Popis: This work aims at elucidating the mechanism and kinetics of hydrolysis of GANT61, the first and most-widely used inhibitor of the Hedgehog (Hh) signalling pathway that targets Glioma-associated oncogene homologue (Gli) proteins, and at confirming the chemical nature of its bioactive form. GANT61 is poorly stable under physiological conditions and rapidly hydrolyses into an aldehyde species (GANT61-A), which is devoid of the biological activity against Hh signalling, and a diamine derivative (GANT61-D), which has shown inhibition of Gli-mediated transcription. Here, we combined chemical synthesis, NMR spectroscopy, analytical studies, molecular modelling and functional cell assays to characterise the GANT61 hydrolysis pathway. Our results show that GANT61-D is the bioactive form of GANT61 in NIH3T3 Shh-Light II cells and SuFu−/− mouse embryonic fibroblasts, and clarify the structural requirements for GANT61-D binding to Gli1. This study paves the way to the design of GANT61 derivatives with improved potency and chemical stability.
Databáze: Directory of Open Access Journals
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