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

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.

Automated summary

Depriving cancer cells of sufficient NAD levels, mainly through interfering with their NAD-producing capacity, has been considered as a promising anti-cancer strategy. However, current inhibitors targeting NAD-producing enzyme NAMPT have limited efficacy in clinical trials, suggesting that alternative NAD-producing enzymes may be utilized by cancer cells. Recent studies have highlighted the relevance of NAPRT as a rate-limiting enzyme in the Preiss-Handler NAD-production pathway in human cancers. In this study, a NAPRT inhibitor, 2-hydroxynicotinic acid, was found to work cooperatively with the NAMPT inhibitor FK866 to kill NAPRT-proficient cancer cells. Furthermore, two additional chemical scaffolds with NAPRT inhibitory activity were identified through high-throughput virtual screening.