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Identification of NAPRT Inhibitors with Anti-Cancer Properties by In Silico Drug Discovery.

Moustafa S GhanemIrene CaffaAlberto Del RioJorge FrancoMarco Daniele ParentiFiammetta MonacelliMichele CeaBy Amr KhalifaAimable NahimanaMichel A DuchosalSilvia RaveraNadia BertolaSantina BruzzoneAlessio NencioniFrancesco Piacente
Published in: Pharmaceuticals (Basel, Switzerland) (2022)
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.
Keyphrases
  • drug discovery
  • high throughput
  • clinical trial
  • cancer therapy
  • endothelial cells
  • drug delivery
  • molecular docking
  • randomized controlled trial
  • electronic health record
  • case control
  • drug induced