期刊
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
卷 33, 期 1, 页码 349-358出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2017.1419221
关键词
GANT61; Hedgehog pathway; Gli inhibitor; chemical stability; bioactive form
资金
- Associazione Italiana Ricerca Cancro (AIRC) [IG14723, IG20801]
- PRIN [2012C5YJSK002]
- Progetti di Ricerca di Universita Sapienza di Roma
- Pasteur Institute/Cenci Bolognetti Foundation
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. [GRAPHICS] .
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