| Autor: |
Moustafa S. Ghanem, Irene Caffa, Alberto Del Rio, Jorge Franco, Marco Daniele Parenti, Fiammetta Monacelli, Michele Cea, Amr Khalifa, Aimable Nahimana, Michel A. Duchosal, Silvia Ravera, Nadia Bertola, Santina Bruzzone, Alessio Nencioni, Francesco Piacente |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Pharmaceuticals, Vol 15, Iss 7, p 848 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
1424-8247 |
| DOI: |
10.3390/ph15070848 |
| Popis: |
Depriving cancer cells of sufficient NAD levels, mainly through interfering with their NAD-producing capacity, has been conceived as a promising anti-cancer strategy. Numerous inhibitors of the NAD-producing enzyme, nicotinamide phosphoribosyltransferase (NAMPT), have been developed over the past two decades. However, their limited anti-cancer activity in clinical trials raised the possibility that cancer cells may also exploit alternative NAD-producing enzymes. Recent studies show the relevance of nicotinic acid phosphoribosyltransferase (NAPRT), the rate-limiting enzyme of the Preiss–Handler NAD-production pathway for a large group of human cancers. We demonstrated that the NAPRT inhibitor 2-hydroxynicotinic acid (2-HNA) cooperates with the NAMPT inhibitor FK866 in killing NAPRT-proficient cancer cells that were otherwise insensitive to FK866 alone. Despite this emerging relevance of NAPRT as a potential target in cancer therapy, very few NAPRT inhibitors exist. Starting from a high-throughput virtual screening approach, we were able to identify and annotate two additional chemical scaffolds that function as NAPRT inhibitors. These compounds show comparable anti-cancer activity to 2-HNA and improved predicted aqueous solubility, in addition to demonstrating favorable drug-like profiles. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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