Discovery and characterization of novel small-molecule inhibitors targeting nicotinamide phosphoribosyltransferase

Xu, Tao; Zhang, Sai-Long; Dong, Guoqiang; Liu, Xin-Zhu; Wang, Xia; Lv, Xiaoqun; Qian, Qijun; Zhang, Ruoyu; Sheng, Chunquan; Miao, Chao‐Yu

doi:10.1038/srep10043

Cited by 45 publications

(59 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[94][95][96] Approximately, 348 compounds with NAMPT activity ,40% and 495 compounds with NAMPT activity .125% at the concentration of 20 mM have been obtained. [94][95][96] Although we have discovered several structurally diverse NAMPT inhibitors with potential to be anticancer agents, 97 the hits of NAMPT activators are still under verification in our laboratory. P7C3 neuroprotective chemicals are a group of compounds with potential to raise NAD concentration through activating of NAMPT.…”

Section: Nampt Activatormentioning

confidence: 99%

NAMPT and NAMPT-controlled NAD Metabolism in Vascular Repair

Wang

Liu

et al. 2016

Journal of Cardiovascular Pharmacology

Self Cite

View full text Add to dashboard Cite

Vascular repair plays important roles in postischemic remodeling and rehabilitation in cardiovascular and cerebrovascular disease, such as stroke and myocardial infarction. Nicotinamide adenine dinucleotide (NAD), a well-known coenzyme involved in electron transport chain for generation of adenosine triphosphate, has emerged as an important controller regulating various biological signaling pathways. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme for NAD biosynthesis in mammals. NAMPT may also act in a nonenzymatic manner, presumably mediated by unknown receptor(s). Rapidly accumulating data in the past decade show that NAMPT and NAMPT-controlled NAD metabolism regulate fundamental biological functions in endothelial cells, vascular smooth muscle cells, and endothelial progenitor cells. The NAD-consuming proteins, including sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38, may contribute to the regulatory effects of NAMPT-NAD axis in these cells and vascular repair. This review discusses the current data regarding NAMPT and NAMPT-controlled NAD metabolism in vascular repair and the clinical potential translational application of NAMPT-related products in treatment of cardiovascular and cerebrovascular disease.

show abstract

Section: Nampt Activatormentioning

confidence: 99%

NAMPT and NAMPT-controlled NAD Metabolism in Vascular Repair

Wang

Liu

et al. 2016

Journal of Cardiovascular Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…With regard to the above‐mentioned positive effects of NAMPT in restoring neurogenesis, targeting NAMPT can be applied as a powerful strategy to treat neurogenesis‐associated disorders. Although novel NAMPT inhibitors have been discovered recently , there is no report about NAMPT activators, except for a recent study demonstrating that P7C3 chemicals activate the NAMPT–NAD pathway . Hence, exploring novel NAMPT activators as candidates to treat neurological diseases is quite essential.…”

Section: Nicotinamide Phosphoribosyltransferase In Neurogenesismentioning

confidence: 99%

Targeting Nicotinamide Phosphoribosyltransferase as a Potential Therapeutic Strategy to Restore Adult Neurogenesis

Wang

2016

CNS Neurosci Ther

Self Cite

View full text Add to dashboard Cite

Adult neurogenesis is the process of generating new neurons throughout life in the olfactory bulb and hippocampus of most mammalian species, which is closely related to aging and disease. Nicotinamide phosphoribosyltransferase (NAMPT), also an adipokine known as visfatin, is the rate-limiting enzyme for mammalian nicotinamide adenine dinucleotide (NAD) salvage synthesis by generating nicotinamide mononucleotide (NMN) from nicotinamide. Recent findings from our laboratory and other laboratories have provided much evidence that NAMPT might serve as a therapeutic target to restore adult neurogenesis. NAMPT-mediated NAD biosynthesis in neural stem/progenitor cells is important for their proliferation, self-renewal, and formation of oligodendrocytes in vivo and in vitro. Therapeutic interventions by the administration of NMN, NAD, or recombinant NAMPT are effective for restoring adult neurogenesis in several neurological diseases. We summarize adult neurogenesis in aging, ischemic stroke, traumatic brain injury, and neurodegenerative disease and review the advances of targeting NAMPT in restoring neurogenesis. Specifically, we provide emphasis on the P7C3 family, a class of proneurogenic compounds that are potential NAMPT activators, which might shed light on future drug development in neurogenesis restoration.

show abstract

“…This suggests that certain types of cancers, which express NNMT at a high level, could potentially be more susceptible to inhibitors of NamPT. Several such inhibitors are currently being tested in clinical studies (23,58). Based on our analyses, it might be reasonable to test patients for NNMT expression in the tumor tissue.…”

Section: Discussionmentioning

confidence: 99%

Identification of evolutionary and kinetic drivers of NAD-dependent signaling

Bockwoldt

Houry

Niere

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Nicotinamide adenine dinucleotide (NAD) provides an important link between metabolism and signal transduction and has emerged as central hub between bioenergetics and all major cellular events. NAD-dependent signaling (e.g., by sirtuins and poly–adenosine diphosphate [ADP] ribose polymerases [PARPs]) consumes considerable amounts of NAD. To maintain physiological functions, NAD consumption and biosynthesis need to be carefully balanced. Using extensive phylogenetic analyses, mathematical modeling of NAD metabolism, and experimental verification, we show that the diversification of NAD-dependent signaling in vertebrates depended on 3 critical evolutionary events: 1) the transition of NAD biosynthesis to exclusive usage of nicotinamide phosphoribosyltransferase (NamPT); 2) the occurrence of nicotinamide N-methyltransferase (NNMT), which diverts nicotinamide (Nam) from recycling into NAD, preventing Nam accumulation and inhibition of NAD-dependent signaling reactions; and 3) structural adaptation of NamPT, providing an unusually high affinity toward Nam, necessary to maintain NAD levels. Our results reveal an unexpected coevolution and kinetic interplay between NNMT and NamPT that enables extensive NAD signaling. This has implications for therapeutic strategies of NAD supplementation and the use of NNMT or NamPT inhibitors in disease treatment.

show abstract

Discovery and characterization of novel small-molecule inhibitors targeting nicotinamide phosphoribosyltransferase

Cited by 45 publications

References 26 publications

NAMPT and NAMPT-controlled NAD Metabolism in Vascular Repair

NAMPT and NAMPT-controlled NAD Metabolism in Vascular Repair

Targeting Nicotinamide Phosphoribosyltransferase as a Potential Therapeutic Strategy to Restore Adult Neurogenesis

Identification of evolutionary and kinetic drivers of NAD-dependent signaling

Contact Info

Product

Resources

About