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Identification of new FK866 analogues with potent anticancer activity against pancreatic cancer
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2022-06-02 , 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 4
Affiliation  

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.



中文翻译:


鉴定对胰腺癌具有有效抗癌活性的新型 FK866 类似物



胰腺导管腺癌(PDAC)是最致命的疾病之一,化疗尚未取得成功。 FK866 (( E )- N -(4-(1-苯甲酰哌啶-4-基)丁基)-3-(吡啶-3-基)丙烯酰胺) 是一种著名的 NAMPT(烟酰胺磷酸核糖基转移酶)抑制剂,具有抗癌活性,但在二期临床试验中失败了。我们发现 FK866 在三种 PDAC 细胞系以及 Jurkat T 细胞白血病细胞中显示出抗增殖活性。合成了超过 50 个 FK866 类似物,这些类似物在 FK866 哌啶苯甲酰胺基团的苯环上引入取代基,并将其丁-1,4-二基链交换为 1-oxyprop-3-yl, ( E )-but-2-en -1,4-二基以及2-和3-碳链。 FK866 的吡啶-3-基部分被替换为氯化和氟化类似物以及吡嗪-2-基和哒嗪-4-基。几种化合物表现出低纳摩尔或亚纳摩尔细胞生长抑制活性。我们最好的细胞抗增殖化合物是 FK866 的 2,4,6-三甲氧基苯甲酰胺类似物 (( E ) -N- (4-(1-(2,4,6-三甲氧基苯甲酰基)哌啶-4-基)丁基)- 3-(吡啶-3-基)丙烯酰胺)( 9 )、2,6-二甲氧基苯甲酰胺( 8 )和2-甲氧基苯甲酰胺( 4 ),其对PDAC细胞的IC 50分别为0.16 nM、0.004 nM和0.08 nM,分别。

更新日期:2022-06-02
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