Nicotinamide phosphoribosyltransferase (NAMPT), also known as pre-B-cell colony-enhancing factor 1 (PBEF1) or visfatin, is the rate-limiting enzyme in mammalian NAD+ biosynthesis from nicotinamide. NAD+ is an essential cofactor involved in many cellular processes like DNA repair, metabolism, cell signaling, and gene regulation. NAMPT catalyzes the first step in the salvage pathway for NAD+ biosynthesis by converting nicotinamide to nicotinamide mononucleotide (NMN). Without NAD+, cells become metabolically dysfunctional and die. Thus, NAMPT plays a crucial role in maintaining NAD+ homeostasis and cellular metabolism.
Dysregulation Of NAD+ Levels In Cancer
Cancer cells have higher metabolic demands compared to normal cells due to their rapid proliferation rates. They upregulate several metabolic pathways like glycolysis, nucleotide biosynthesis, and lipid synthesis to support their growth and survival. Studies have shown that NAD+ levels are significantly higher in many cancer types, including leukemia, lung cancer, breast cancer, and prostate cancer. The increased NAD+ levels in cancer cells are maintained by the overexpression of NAMPT. NAMPT Inhibitors reduces NAD+ levels in cancer cells and suppresses their growth and survival. Hence, NAMPT has emerged as an attractive therapeutic target for cancer treatment.
NAMPT Inhibitors As Potential Anticancer Agents
Several small molecule inhibitors of NAMPT have been developed and tested against various cancer models. The first Nicotinamide phosphoribosyltransferase inhibitors to enter clinical trials was FK866 (apostat). It demonstrated robust anticancer activity in preclinical studies across several tumor types without obvious toxicity. However, clinical trials of FK866 had to be discontinued due to pharmacokinetic issues. Another Nicotinamide phosphoribosyltransferase inhibitors, GMX1778, showed encouraging results against acute myeloid leukemia and solid tumors in phase 1 clinical studies but its development was also halted. Third-generation Nicotinamide phosphoribosyltransferase inhibitors like CHS-828, GNE-617, and THN-102 are currently being evaluated in early-phase clinical trials against hematological and solid tumors, with favorable safety profiles observed so far. Nicotinamide phosphoribosyltransferase inhibitors work by depleting NAD+ levels in cancer cells and hindering their metabolic and bioenergetic functions. They have shown single-agent activity as well as synergistic effects when combined with chemotherapy or molecularly targeted drugs. With continued development efforts, Nicotinamide phosphoribosyltransferase inhibitors hold promise as a new class of targeted anticancer drugs.
Role Of NAMPT-NAD+ Axis In Inflammation And Immunometabolism
In addition to cancer, dysfunction of the NAMPT-NAD+ axis has been implicated in several chronic inflammatory and autoimmune disorders. Levels of NAMPT and NAD+ are known to increase in immune cells in response to inflammatory stimuli. NAD+ regulates the activity of various immunometabolic enzymes and mediates the production of inflammatory cytokines. For example, the enzyme CD38 controls NAD+ breakdown to cyclic ADP-ribose and controls the activation and functions of immune cells. NAMPT is essential for maintaining NAD+ levels in immune cells and supporting pro-inflammatory macrophage polarization. Blocking NAMPT activity using inhibitors has shown to suppress macrophage-driven inflammation in mouse models of colitis, atherosclerosis, and arthritis. Thus, NAMPT inhibitors inhibitors could represent a novel immunometabolic strategy for treating inflammatory disorders by modulating immune cell metabolism and functions.
Nicotinamide Phosphoribosyltransferase Inhibitors And Their Therapeutic Potential In Other Diseases
Besides cancer and inflammation, the NAMPT-NAD+ pathway has emerged as a potential therapeutic target for various other diseases characterized by metabolic dysregulation and oxidative stress. Aging is associated with a progressive decline in NAD+ levels. Studies suggest that maintaining NAD+ levels using Nicotinamide phosphoribosyltransferase inhibitors or NAD+ precursors could ameliorate age-associated metabolic and functional decline. NAMPT inhibition also holds promise for treating neurodegenerative disorders like Alzheimer’s and Parkinson’s disease by protecting neurons from oxidative damage and metabolic dysfunction. Further, in metabolic diseases like obesity, diabetes and non-alcoholic fatty liver disease, excessive NAMPT expression contributes to insulin resistance, adipose tissue inflammation and liver damage. Targeting the NAMPT axis could aid in restoring metabolic homeostasis and mitigating disease pathogenesis. Though still in early stages of development, Nicotinamide phosphoribosyltransferase inhibitors offer a multifaceted therapeutic strategy for improving healthspan and managing diverse pathologies by modulating cellular NAD+ metabolism.
Optimizing NAMPT Inhibitors Specificity And CNS Delivery
Despite the translational potential of Nicotinamide phosphoribosyltransferase inhibitors their clinical development faces two key challenges- lack of specificity and poor CNS penetration. NAMPT shares structural homology with other cytosolic5′-nucleotidases which hampers the specificity of initial inhibitor chemotypes. This partially contributed to off-target toxicity issues observed with early Nicotinamide phosphoribosyltransferase inhibitors. More selective second and third-generation inhibitors are being designed based on detailed structure-activity studies to minimize cross-reactivity. Additionally, most Nicotinamide phosphoribosyltransferase inhibitors have difficulty crossing the blood-brain barrier, limiting their applications for neurologic disorders. Novel prodrug and nanoparticle-mediated formulations are being explored to achieve optimal CNS exposures of Nicotinamide phosphoribosyltransferase inhibitors without impairing peripheral tissue distribution. Addressing issues of target selectivity and CNS bioavailability will be critical to fully.
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1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
About Author – Alice Mutum
Alice Mutum is a seasoned senior content editor at Coherent Market Insights, leveraging extensive expertise gained from her previous role as a content writer. With seven years in content development, Alice masterfully employs SEO best practices and cutting-edge digital marketing strategies to craft high-ranking, impactful content. As an editor, she meticulously ensures flawless grammar and punctuation, precise data accuracy, and perfect alignment with audience needs in every research report. Alice’s dedication to excellence and her strategic approach to content make her an invaluable asset in the world of market insights. LinkedIn