Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

Abstract

Nicotinamide adenine dinucleotide (NAD) is a cofactor of many enzymatic reactions as well as being a substrate for a number of NAD-consuming enzymes (e.g., PARPS, sirtuins, etc). NAD can be synthesized de novo starting from tryptophan, nicotinamide, nicotinic acid, or nicotinamide riboside from the diet. On the other hand, the nicotinamide that is liberated by NAD-consuming enzymes can be salvaged to reform NAD. In this former instance, nicotinamide phosphoribosyltransferase (NAMPT) is the bottleneck enzyme. In the many cells in which the salvage pathway is predominant, NAMPT, therefore, represents an important controller of intracellular NAD concentrations, and as a consequence of energy metabolism. It is, therefore, not surprising that NAMPT is over expressed by tumoral cells, which take advantage from this to sustain growth rate and tumor progression. This has led to the initiation of numerous medicinal chemistry programs to develop NAMPT inhibitors in the context of oncology. More recently, however, it has been shown that NAMPT inhibitors do not solely target the tumor but also have an effect on the immune system. To add complexity, this enzyme can also be secreted by cells, and in the extracellular space it acts as a cytokine mainly through the activation of Toll like Receptor 4 (TLR4), although it has not been clarified yet if this is the only receptor responsible for its actions. While specific small molecules have been developed only against the intracellular form of NAMPT, growing evidences sustain the possibility to target the extracellular form. In this contribution, the most recent evidences on the medicinal chemistry of NAMPT will be reviewed, together with the key elements that sustain the hypothesis of NAMPT targeting and the drawbacks so far encountered.

Role of secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) in prostate cancer progression: Novel biomarker and therapeutic target

“…Silencing NAMPT expression sensitizes tumors to chemotherapeutic agents [49] supporting NAMPT as a clinically-relevant therapeutic target. Prior targeting of NAMPT for cancer treatment has been focused on developing agents that inhibit iNAMPT enzymatic activity and regulation of biosynthesis of NAD via a salvage pathway with the synthesis of nicotinamide mononucleotide (NMN) from nicotinamide (NAM) and phosphoribosyl pyrophosphate (PRPP) [ 12 , 50 ]. iNAMPT enzymatic inhibitors (GMX-1776 or CHS-828, APO-866 aka Daporinad or FK866), have been developed as anti-cancer treatment options.…”

“…NAMPT-mediated NAD biosynthesis controls the functions of mammalian sirtuin family members, as well as other NAD-consuming enzymes, such as PARPs, in each subcellular compartment, therefore, involving in a variety of critical biological processes, including cell metabolism and stress response [ 8 , 9 ]. In contrast to iNAMPT, we previously have shown that the extracellularly-secreted NAMPT ( eNAMPT) is a key innate immunity regulator and potent damage-associated molecular pattern protein (DAMP) responding to potentially injurious danger signals [10] , [11] , [12] via ligation of Toll-like receptor 4 (TLR4) and activation of this evolutionarily-conserved inflammatory cascade [10] .…”

Mono(ADP-ribosyl)ation Enzymes and NAD+ Metabolism: A Focus on Diseases and Therapeutic Perspectives

“…NAMPT and NAPRT can be secreted extracellularly (eNAMPT, eNAPRT) as cytokines and damage-associated molecular patterns (DAMPs): eNAMPT is known as pre-B cell colony-enhancing factor or visfatin [ 40 ], acting through the activation of Toll-like receptor 4 (TLR4) [ 41 ]. The enzyme is involved in human inflammation, obesity, diabetes and has been indicated as a target for anticancer and immunotherapy strategy [ 41 ]: moreover, eNAPRT is a biomarker of sepsis and septic shock [ 42 ].…”

Interplay between Cellular Metabolism and the DNA Damage Response in Cancer

“…They have a specific dependency on either NAMPT or NAPRT, depending on the cancer type [34], and cells treated with inhibitors of either of these two enzymes show enhanced susceptibility to oxidative stress [35][36][37]. Untransformed cells are less sensitive to ROS induction upon NAMPT inhibition, suggesting a therapeutic window that can be used to target a specific vulnerability in cancer cells [38,39]. Moreover, cytotoxicity induced by glucose deprivation is enhanced in cancer cells and is mediated by increased steady-state levels of ROS [40].…”