Synthesis and structure-activity relationship of new nicotinamide phosphoribosyltransferase inhibitors with antitumor activity on solid and haematological cancer

Fratta, Simone; Biniecka, Paulina; Vargas, Ângelo; Carmona, Ana T.; Nahimana, Aimable; Duchosal, Michel A.; Piacente, Francesco; Bruzzone, Santina; Caffa, Irene; Nencioni, Alessio; Robina, Inmaculada

doi:10.1016/j.ejmech.2023.115170

Cited by 5 publications

(3 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have also recently reviewed the preclinical and clinical aspects of NAD +lowering drugs, with a special focus on NAMPT inhibitors, including their downstream effects and their optimization strategies [8]. Here, we will just remind the reader that the last two years have witnessed the emergence of new small-molecule chemical NAMPT inhibitors that exhibited very potent anticancer activity against hematological malignancies with IC50 values in the picomolar range [56][57][58]. A synergistic interaction between FK866 and the antidiabetic drug metformin was also recently reported in pancreatic cancer cells [59].…”

Section: Targeting Nicotinamide Phosphoribosyltransferasementioning

confidence: 99%

Inhibitors of NAD+ Production in Cancer Treatment: State of the Art and Perspectives

Ghanem,

Caffa,

Monacelli

et al. 2024

IJMS

Self Cite

View full text Add to dashboard Cite

The addiction of tumors to elevated nicotinamide adenine dinucleotide (NAD+) levels is a hallmark of cancer metabolism. Obstructing NAD+ biosynthesis in tumors is a new and promising antineoplastic strategy. Inhibitors developed against nicotinamide phosphoribosyltransferase (NAMPT), the main enzyme in NAD+ production from nicotinamide, elicited robust anticancer activity in preclinical models but not in patients, implying that other NAD+-biosynthetic pathways are also active in tumors and provide sufficient NAD+ amounts despite NAMPT obstruction. Recent studies show that NAD+ biosynthesis through the so-called “Preiss-Handler (PH) pathway”, which utilizes nicotinate as a precursor, actively operates in many tumors and accounts for tumor resistance to NAMPT inhibitors. The PH pathway consists of three sequential enzymatic steps that are catalyzed by nicotinate phosphoribosyltransferase (NAPRT), nicotinamide mononucleotide adenylyltransferases (NMNATs), and NAD+ synthetase (NADSYN1). Here, we focus on these enzymes as emerging targets in cancer drug discovery, summarizing their reported inhibitors and describing their current or potential exploitation as anticancer agents. Finally, we also focus on additional NAD+-producing enzymes acting in alternative NAD+-producing routes that could also be relevant in tumors and thus become viable targets for drug discovery.

show abstract

Section: Targeting Nicotinamide Phosphoribosyltransferasementioning

confidence: 99%

Inhibitors of NAD+ Production in Cancer Treatment: State of the Art and Perspectives

Ghanem,

Caffa,

Monacelli

et al. 2024

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“… 127 , 128 , 129 Inhibiting NAMPT has been shown to reduce NAD + levels, leading to cancer cell death and impeding tumor growth. 127 Several NAMPT inhibitors, such as FK866, GMX1778, CHS828, 130 and OT-82, 124 have been developed and are currently undergoing clinical trials to assess their efficacy in treating various types of cancer. 131 Nicotinamide riboside kinase 1/2 are enzymes involved in the alternative NAD + synthesis pathway that phosphorylates nicotinamide riboside to form NAD + .…”

Section: Regulation Of Mnadkmentioning

confidence: 99%

Homeostatic regulation of NAD(H) and NADP(H) in cells

Chen,

Xing,

Zhang

et al. 2024

Genes & Diseases

View full text Add to dashboard Cite

“…However, the low activities of the natural NAMPTs and the inhibitory effect of byproducts pyrophosphoric acid (PPi) on enzyme activity have greatly hampered its industrial applications. − The main characteristic of the two main substrates toward NAMPT is large side chains with a circular structure. In addition, the activity of NAMPT is commonly suppressed by specific small-molecule compounds, and these inhibitory effects are intricately linked to the protein structure of the enzyme. , The byproduct PPi comprises two tetrahedral structures formed by phosphate groups, and it has a similar side-chain structure of the substrate, which may hinder the substrate from entering the enzyme active center. Therefore, the current challenge lies in the large volume of the substrate with side chains and byproducts in the substitution reaction occupying the curved and single substrate channel, which limited the catalytic efficiency of the enzyme.…”

Section: Introductionmentioning

confidence: 99%

Design of NAMPTs with Superior Activity by Dual-Channel Protein Engineering Strategy

Peng,

Shen,

Zou

et al. 2024

J. Agric. Food Chem.

View full text Add to dashboard Cite

The nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed substitution reaction plays a pivotal role in the biosynthesis of nucleotide compounds. However, industrial applications are hindered by the low activity of NAMPTs. In this study, a novel dual-channel protein engineering strategy was developed to increase NAMPT activity by enhancing substrate accessibility. The best mutant (CpNAMPT Y13G+Y15S+F76P ) with a remarkable 5-fold increase in enzyme activity was obtained. By utilizing CpNAMPT Y13G+Y15S+F76P as a biocatalyst, the accumulation of β-nicotinamide mononucleotide reached as high as 19.94 g L −1 within 3 h with an impressive substrate conversion rate of 99.8%. Further analysis revealed that the newly generated substrate channel, formed through crack propagation, facilitated substrate binding and enhanced byproduct tolerance. In addition, three NAMPTs from different sources were designed based on the dual-channel protein engineering strategy, and the corresponding dual-channel mutants with improved enzyme activity were obtained, which proved the effectiveness and practicability of the approach.

show abstract

Synthesis and structure-activity relationship of new nicotinamide phosphoribosyltransferase inhibitors with antitumor activity on solid and haematological cancer

Cited by 5 publications

References 39 publications

Inhibitors of NAD+ Production in Cancer Treatment: State of the Art and Perspectives

Inhibitors of NAD+ Production in Cancer Treatment: State of the Art and Perspectives

Homeostatic regulation of NAD(H) and NADP(H) in cells

Design of NAMPTs with Superior Activity by Dual-Channel Protein Engineering Strategy

Contact Info

Product

Resources

About