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Identification of new FK866 analogues with potent anticancer activity against pancreatic cancer
Jian-Fei Bai1, Somi Reddy Majjigapu1, Bernard Sordat1
1Laboratory of Glycochemistry and Asymmetric Synthesis, Swiss Institute of Technology (EPFL), 1015, Lausanne, Switzerland.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases for which chemotherapy has not been very successful yet. FK866 ((E)-N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) is a well-known NAMPT (nicotinamide phosphoribosyltransferase) inhibitor with anti-cancer activities, but it failed in phase II clinical trials. We found that FK866 shows anti-proliferative activity in three PDAC cell lines, as well as in Jurkat T-cell leukemia cells. More than 50 FK866 analogues were synthesized that introduce substituents on the phenyl ring of the piperidine benzamide group of FK866 and exchange its buta-1,4-diyl tether for 1-oxyprop-3-yl, (E)-but-2-en-1,4-diyl and 2- and 3-carbon tethers. The pyridin-3-yl moiety of FK866 was exchanged for chlorinated and fluorinated analogues and for pyrazin-2-yl and pyridazin-4-yl groups. Several compounds showed low nanomolar or sub-nanomolar cell growth inhibitory activity. Our best cell anti-proliferative compounds were the 2,4,6-trimethoxybenzamide analogue of FK866 ((E)-N-(4-(1-(2,4,6-trimethoxybenzoyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) (9), the 2,6-dimethoxybenzamide (8) and 2-methoxybenzamide (4), which exhibited an IC50 of 0.16 nM, 0.004 nM and 0.08 nM toward PDAC cells, respectively.
Insights
New FK866 analogues show potent anti-proliferative activity against pancreatic cancer. These novel compounds, including methoxybenzamide derivatives, exhibit sub-nanomolar IC50 values, offering promise for pancreatic ductal adenocarcinoma treatment.
Area of Science:
- Medicinal Chemistry
- Oncology
- Biochemistry
Background:
- Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with limited chemotherapy options.
- FK866, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, demonstrated anti-cancer effects but failed in clinical trials.
- Targeting NAMPT is a viable strategy for cancer therapy.
Purpose of the Study:
- To synthesize and evaluate novel FK866 analogues with enhanced anti-proliferative activity against PDAC.
- To identify structural modifications that improve potency and overcome limitations of the parent compound.
Main Methods:
- Synthesis of over 50 FK866 analogues with modifications to the benzamide phenyl ring, tether, and pyridinyl moiety.
- Assessment of cell growth inhibitory activity using IC50 values in PDAC and Jurkat T-cell leukemia cell lines.
Main Results:
- Several FK866 analogues displayed potent cell growth inhibition in the low nanomolar to sub-nanomolar range.
- The 2,4,6-trimethoxybenzamide analogue (9) showed an IC50 of 0.16 nM.
- The 2,6-dimethoxybenzamide (8) and 2-methoxybenzamide (4) analogues exhibited IC50 values of 0.004 nM and 0.08 nM, respectively.
Conclusions:
- Novel FK866 analogues, particularly methoxybenzamide derivatives, possess significant anti-proliferative activity against PDAC cells.
- These compounds represent promising candidates for further development as pancreatic cancer therapeutics.
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