Title:Pharmacological Inhibitors of NAD Biosynthesis as Potential An ticancer Agents
Volume: 12
Issue: 3
Author(s): Stephanie Lucas, Claire Soave, Ghazal Nabil, Zainab Sabry Othman Ahmed, Guohua Chen, Hossny Awad El-Banna, Q. Ping Dou* Jian Wang*
Affiliation:
- Department of Oncology, Wayne State University, 4100 John R Road, Detroit, MI 48201,United States
- Department of Pathology, Wayne State University, 540 E. Canfield Road, Detroit, MI 48201,United States
Keywords:
Cancer metabolism, IDO, NAD+, NAD+ biosynthesis, NAMPT, pharmacological inhibitor, TDO, Warburg effect.
Abstract: Background: Alteration of cellular metabolism is a hallmark of cancer, which underlies
exciting opportunities to develop effective, anti-cancer therapeutics through inhibition of cancer metabolism.
Nicotinamide Adenine Dinucleotide (NAD+), an essential coenzyme of energy metabolism
and a signaling molecule linking cellular energy status to a spectrum of molecular regulation, has been
shown to be in high demand in a variety of cancer cells. Depletion of NAD+ by inhibition of its key
biosynthetic enzymes has become an attractive strategy to target cancer.
Objective and Method: 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.
