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

  • Eur J Med Chem. 2022 Sep 5;239:114504. doi: 10.1016/j.ejmech.2022.114504.
Jian-Fei Bai  1 ,  Somi Reddy Majjigapu  1 ,  Bernard Sordat  1 ,  Sophie Poty  1 ,  Pierre Vogel  1 ,  Pilar Elías-Rodríguez  2 ,  Antonio J Moreno-Vargas  2 ,  Ana T Carmona  2 ,  Irene Caffa  3 ,  Moustafa Ghanem  3 ,  Amr Khalifa  4 ,  Fiammetta Monacelli  4 ,  Michele Cea  4 ,  Inmaculada Robina  2 ,  Consuelo Gajate  5 ,  Faustino Mollinedo  5 ,  Axel Bellotti  6 ,  Aimable Nahimana  6 ,  Michel Duchosal  7 ,  Alessio Nencioni  8
Affiliations
  • 1. Laboratory of Glycochemistry and Asymmetric Synthesis, Swiss Institute of Technology (EPFL), 1015, Lausanne, Switzerland.
  • 2. Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Sevilla, 41012, Spain.
  • 3. Department of Internal Medicine and Medical Specialties, University of Genoa, 16132, Genoa, Italy.
  • 4. Department of Internal Medicine and Medical Specialties, University of Genoa, 16132, Genoa, Italy; Ospedale Policlinico San Martino IRCCS, Genoa, Italy.
  • 5. Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
  • 6. Central Laboratory of Hematology, Medical Laboratory and Pathology Department, Lausanne University Hospital, 1011, Lausanne, Switzerland.
  • 7. Central Laboratory of Hematology, Medical Laboratory and Pathology Department, Lausanne University Hospital, 1011, Lausanne, Switzerland; Service of Hematology, Oncology Department, Lausanne University Hospital, 1011, Lausanne, Switzerland.
  • 8. Department of Internal Medicine and Medical Specialties, University of Genoa, 16132, Genoa, Italy; Ospedale Policlinico San Martino IRCCS, Genoa, Italy. Electronic address: [email protected].
PMID: 35724566 DOI: 10.1016/j.ejmech.2022.114504
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.

Keywords
Cell culture; NAD(+); NAMPT; Pancreatic ductal adenocarcinoma; Piperidine carboxamides.
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