Anticancer Activities of Novel Nicotinamide Phosphoribosyltransferase Inhibitors in Hematological Malignancies

Biniecka, Paulina; Matsumoto, Saki; Belotti, Axel; Joussot, Jessie; Bai, Jian‐Fei; Majjigapu, Somi Reddy; Thoueille, Paul; Spaggiari, Dany; Desfontaine, Vincent; Piacente, Francesco; Bruzzone, Santina; Cea, Michele; Décosterd, Laurent A.; Vogel, Pierre; Nencioni, Alessio; Duchosal, Michel A.; Nahimana, Aimable

doi:10.3390/molecules28041897

Cited by 2 publications

(1 citation statement)

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“…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

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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.

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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

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New Analogues of the Nicotinamide Phosphoribosyltransferase Inhibitor FK866 as Potential Anti-Pancreatic Cancer Agents

Conforti,

Benzi,

Caffa

et al. 2024

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Background: During the past two decades, many nicotinamide phosphoribosyltransferase (NAMPT) inhibitors were prepared and tested because this enzyme is overexpressed in pancreatic cancer. Although FK866 is a well-known, strong NAMPT inhibitor, it suffers severe drawbacks. background: During the past two decades, many nicotinamide phosphoribosyltransferase (NAMPT) inhibitors were prepared and tested because this enzyme is overexpressed in pancreatic cancer. Although FK866 is a well-known, strong NAMPT inhibitor, it suffers from severe drawbacks. Objective: Our work aimed to synthesize efficient NAMPT inhibitors featuring better pharmacokinetic properties than the pyridine-containing FK866. To this aim, the new anticancer agents were based on benzene, pyridazine, or benzothiazole moieties as a cap group instead of the pyridine unit found in FK866 and other NAMPT inhibitors. Methods: The new compounds, prepared exploiting standard heterocycle chemistry and coupling reactions (e.g., formation of amides, ureas, and cyanoguanidines, copper-mediated azide-alkyne cycloaddition), have been fully characterized using NMR and HRMS analyses. Their activity has been evaluated using cytotoxicity and intracellular NAD depletion assays in the human pancreatic cancer cell line MiaPaCa-2. Results: Among the 14 products obtained, compound 28, bearing a pyridazine unit as the cap group and a thiophene moiety as the tail group, showed 6.7 nanomolar inhibition activity in the intracellular NAD depletion assay and 43 nanomolar inhibition in the MiaPaCa-2 cells cytotoxicity assay, comparable to that observed for FK866. result: Among the 14 products obtained, one showed nanomolar inhibition activity in both biological assays, comparable to that observed for FK866. Conclusion: The positive results observed for some newly synthesized molecules, particularly those carrying a thiophene unit as a tail group, indicate that they could act as in vivo anti-pancreatic cancer agents.

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Anticancer Activities of Novel Nicotinamide Phosphoribosyltransferase Inhibitors in Hematological Malignancies

Cited by 2 publications

References 50 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

New Analogues of the Nicotinamide Phosphoribosyltransferase Inhibitor FK866 as Potential Anti-Pancreatic Cancer Agents

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