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New Analogues of the Nicotinamide Phosphoribosyltransferase Inhibitor FK866 as Potential Anti-Pancreatic Cancer
Irene Conforti1, Andrea Benzi2, Irene Caffa3,4
1Institut des Biomolécules Max Mousseron (IBMM, UMR 5247), Université de Montpellier, Pôle Chimie Balard Recherche, 1919 Route de Mende, 34293 Montpellier, France.
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.
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.
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.
Insights
Researchers developed new nicotinamide phosphoribosyltransferase (NAMPT) inhibitors to treat pancreatic cancer, aiming for improved properties over existing drugs. Compound 28, featuring a pyridazine cap and thiophene tail, showed promising activity, suggesting potential as an in vivo anti-pancreatic cancer agent.
Area of Science:
- Medicinal Chemistry
- Oncology
Background:
- Nicotinamide phosphoribosyltransferase (NAMPT) is overexpressed in pancreatic cancer, making it a therapeutic target.
- Existing NAMPT inhibitors like FK866 have limitations, necessitating the development of improved agents.
Purpose of the Study:
- To synthesize novel NAMPT inhibitors with enhanced pharmacokinetic properties compared to pyridine-based FK866.
- To explore benzene, pyridazine, and benzothiazole moieties as alternative cap groups for NAMPT inhibitors.
Main Methods:
- Synthesized novel compounds using standard heterocycle chemistry and coupling reactions.
- Characterized compounds via NMR and HRMS.
- Assessed activity through cytotoxicity and intracellular NAD depletion assays in MiaPaCa-2 cells.
Main Results:
- 14 new compounds were synthesized and evaluated.
- Compound 28, with a pyridazine cap and thiophene tail, demonstrated potent NAMPT inhibition (6.7 nM) and cytotoxicity (43 nM) in MiaPaCa-2 cells.
- Activity of compound 28 was comparable to the established inhibitor FK866.
Conclusions:
- Newly synthesized molecules, particularly those with a thiophene tail, show potential as effective in vivo anti-pancreatic cancer agents.
- The developed compounds represent promising leads for pancreatic cancer therapy.
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