Identification of new FK866 analogues with potent anticancer activity against pancreatic cancer.

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.

• Authors: Jian-Fei Bai, Somi Reddy Majjigapu, Bernard Sordat, Sophie Poty, Pierre Vogel, Pilar Elías-Rodríguez, Antonio J Moreno-Vargas, Ana T Carmona, Irene Caffa, Moustafa Ghanem, Amr Khalifa, Fiammetta Monacelli, Michele Cea, Inmaculada Robina, Consuelo Gajate, Faustino Mollinedo, Axel Bellotti, Aimable Nahimana, Michel Duchosal, Alessio Nencioni
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 239 Pg. 114504 (Sep 05 2022) ISSN: 1768-3254 [Electronic] France
• PMID: 35724566 (Publication Type: Journal Article)
• Copyright: Copyright © 2022. Published by Elsevier Masson SAS.

Chemical References

• Acrylamides
• Antineoplastic Agents
• Cytokines
• N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
• Piperidines

Topics

• Acrylamides (chemistry, pharmacology)
• Antineoplastic Agents (pharmacology)
• Carcinoma, Pancreatic Ductal (drug therapy)
• Cytokines
• Humans
• Pancreatic Neoplasms (drug therapy)
• Piperidines (chemistry, pharmacology)