2. Academic Validation
  3. Identification of new FK866 analogues with potent anticancer activity against pancreatic cancer

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-147838
    NAMPT Inhibitor