Identification of new FK866 analogues with potent anticancer activity against pancreatic cancer
| Autor: | 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 |
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| Přispěvatelé: | European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Associazione Italiana per la Ricerca sul Cancro, Bai, Jian-Fei [0000-0002-9128-5819], Majjigapu, Somi Reddy [0000-0001-6422-5223], Poty, Sophie [0000-0002-5496-0758], Elías-Rodríguez, Pilar [0000-0002-9117-3905], Moreno-Vargas, Antonio J. [0000-0002-5771-2012], Carmona, Ana T. [0000-0003-1058-7127], Caffa, Irene [0000-0003-1111-9915], Khalifa, Amr [0000-0002-2131-5496], Monacelli, Fiammetta [0000-0003-4303-7252], Cea, Michele [0000-0002-1530-6729], Robina, Inmaculada [0000-0003-1447-8032], Gajate, Consuelo [0000-0003-0604-6459], Mollinedo, Faustino [0000-0002-4939-2434], Nahimana, Aimable [0000-0003-4968-3167], Duchosal, Michel [0000-0003-0543-3449], Nencioni, Alessio [0000-0001-5068-8884], Bai, Jian-Fei, Majjigapu, Somi Reddy, Poty, Sophie, Elías-Rodríguez, Pilar, Moreno-Vargas, Antonio J., Carmona, Ana T., Caffa, Irene, Khalifa, Amr, Monacelli, Fiammetta, Cea, Michele, Robina, Inmaculada, Gajate, Consuelo, Mollinedo, Faustino, Nahimana, Aimable, Duchosal, Michel, Nencioni, Alessio |
| Rok vydání: | 2022 |
| Předmět: |
pancreatic ductal adenocarcinoma
mechanism Antineoplastic Agents NAMPT nad(+) Pancreatic ductal adenocarcinoma Piperidines NAD+ Piperidine carboxamides Drug Discovery Humans apo866 nampt Pharmacology Acrylamides cell culture depletion Organic Chemistry gemcitabine crystal-structure piperidine carboxamides General Medicine sensitivity inhibition Pancreatic Neoplasms nicotinamide phosphoribosyltransferase Cytokines decreases Cell culture Carcinoma Pancreatic Ductal |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | 11 p.- 2 fig.-4 tab.-8 schem.-1 graph. abst. 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. The research leading to these results has received funding from the European Community's Seventh Framework Programme [FP7-2007-2013] under grant agreement no. 256986 (PANACREAS), from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 813284 (INTEGRATA), by the Spanish Ministry of Science, Innovation, and Universities (SAF2017-89672-R) and by the Associazione Italiana per la Ricerca sul Cancro (AIRC), IG#22098. |
| Databáze: | OpenAIRE |
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