Discovery of novel enasidenib analogues targeting inhibition of mutant isocitrate dehydrogenase 2 as antileukaemic agents. (31st December 2023)

• Record Type: Journal Article
• Authors: Khalil, Ahmed F.; El-Moselhy, Tarek F.; El-Bastawissy, Eman A.; Abdelhady, Rasha; Younis, Nancy S.; El-Hamamsy, Mervat H.
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 38:Number 1(2023)
• Publication Date: 2023-12-31
• Subjects: Synthesis -- triazine -- hydrazine -- IDH2 -- enasidenib -- leukaemia -- anticancer; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2022.2157411
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: Mutant isocitrate dehydrogenase (IDH) 2 "IDH2m" acquires a neo-enzymatic activity reducing α-ketoglutarate to an oncometabolite, D-2-hydroxyglutarate (2-HG). Three s -triazine series were designed and synthesised using enasidenib as a lead compound. In vitro anticancer screening via National Cancer Institute "NCI" revealed that analogues 6a, 6c, 6d, 7g, and 7l were most potent, with mean growth inhibition percentage "GI%" = 66.07, 66.00, 53.70, 35.10, and 81.15, respectively, followed by five-dose screening. Compounds 6c, 6e, and 7c were established as the best IDH2 R140Q inhibitors compared to enasidenib, reporting IC50 = 101.70, 67.01, 88.93, and 75.51 nM, respectively. More importantly, 6c, 6e, and 7c displayed poor activity against the wild-type IDH2, IC50 = 2928, 2295, and 3128 nM, respectively, which implementing high selectivity and accordingly safety. Furthermore, 6c was screened for cell cycle arrest, apoptosis induction, and western blot analysis. Finally, computational tools were applied to predict physicochemical properties and binding poses in IDH2 R140Q allosteric site.