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

Antonia Iazzetti, Andrea Calcaterra, Valentina Iovine, Deborah Quaglio, Ilaria D’Acquarica, Alessia Ciogli, Romina Alfonsi, Ludovica Lospinoso Severini, Paola Infante, Lucia Di Marcotullio, Mattia Mori, Francesca Ghirga

Risultato della ricerca: Contributo in rivistaArticolo in rivista

Abstract

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.
Lingua originaleEnglish
pagine (da-a)349-358
Numero di pagine10
RivistaJournal of Enzyme Inhibition and Medicinal Chemistry
Volume33
DOI
Stato di pubblicazionePubblicato - 2018

Keywords

  • Animals
  • Dose-Response Relationship, Drug
  • Fibroblasts
  • GANT61
  • Gli inhibitor
  • Hedgehog Proteins
  • Hedgehog pathway
  • Hydrolysis
  • Kinetics
  • Mice
  • Models, Molecular
  • Molecular Structure
  • NIH 3T3 Cells
  • Pyridines
  • Pyrimidines
  • Signal Transduction
  • Structure-Activity Relationship
  • bioactive form
  • chemical stability

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