Pharmacological Inhibitors of NAD Biosynthesis as Potential An ticancer Agents

Abstract

The main objective of this article is to review the recent patents which develop and implicate the chemical inhibitors of the key NAD+ biosynthetic enzymes for cancer treatment. We first discuss the biological principles of NAD+ metabolism in normal and malignant cells, with a focus on the feasibility of selectively targeting cancer cells by pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT) and indoleamine/tryptophan 2,3-dioxygenases (IDO/TDO), the rate-limiting salvage and de novo NAD+ biosynthetic enzymes, respectively. We then analyze a series of recent patents on development and optimization of chemical scaffolds for inhibiting NAMPT or IDO/TDO enzymes as potential anticancer drugs. Conclusion and Results: We have reviewed 16 relevant patents published since 2015, and summarized the chemical properties, mechanisms of action and proposed applications of the patented compounds. Without a better understanding of the properties of these compounds, their utility for further optimization and clinical use is unknown. For the compounds that have been tested using cell and mouse models of cancer, results look promising and clinical trials are currently ongoing to see if these results translate to improved cancer treatments.

NAMPT Is a Potent Oncogene in Colon Cancer Progression that Modulates Cancer Stem Cell Properties and Resistance to Therapy through Sirt1 and PARP

“…NAMPT inhibition also leads to the attenuation of glycolysis, which results in further perturbation of carbohydrate metabolism in cancer cells (11). Therefore, NAMPT has been proposed as a promising anticancer target (12,13).…”

Implications of NAD+ Metabolism in the Aging Retina and Retinal Degeneration

“…NAMPT is overexpressed in many different types of tumors, and its expression appears to be associated with cancer progression [22,88]. Thus, many cancer biologists have explored the strategy of inhibiting NAMPT expression as a means of reducing tumor growth [88][89][90]. Although preclinical studies have shown this approach to be very beneficial for reducing various tumor types, this anticancer benefit is associated, unfortunately, with severe retinal toxicity.…”

Nicotinamide phosphoribosyltransferase inhibitor ameliorates mouse aging-induced cognitive impairment

“…Therefore, NAMPT inhibitors including FK866 were originally developed as anti-cancer drugs. [23][24][25] Yet, it has been shown that NAMPT inhibitors also exert potent anti-inflammatory effects in the peripheral system. 26,27 We and others have shown that NAMPT inhibitors have neuroprotective effects, mainly through their anti-neuroinflammation effects.…”