Discovery of novel enasidenib analogues targeting inhibition of mutant isocitrate dehydrogenase 2 as antileukaemic agents

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 IC 50 = 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, IC 50 = 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.

Recent biological applications of heterocyclic hybrids containing s-triazine scaffold

“…Cell growth inhibition (GI%) with a 10 mM dose can be summed up as, CCRF-CEM = 79.05, SR = 92.07, NCI-H522 = 1). 58 Thiophene clubbed s-triazine derivatives (52) were synthesized as anticancer agents and their biological activities were evaluated against human lung adenocarcinoma cells (A549). 59 pIC 50 of the series ranged from 4.29 to 6.70, enlightening the range of their potency.…”

Identification of 3‐(5‐cyano‐6‐oxo‐pyridin‐2‐yl)benzenesulfonamides as novel anticancer agents endowed with EGFR inhibitory activity

“…The most effective cyanopyridin-2-one sulfonamides (6e and 6l) were chosen to better understand their cellular mechanisms of action. The DNA concentration was measured using flow cytometry [50][51][52] after HeLa cells were treated with DMSO (control) or compounds 6e and 6l. The results are shown in Figure 3.…”

Experimental Insights into the Interplay between Histone Modifiers and p53 in Regulating Gene Expression

“…com/article/10.3390/ijms241311032/s1. References [97,[102][103][104][105][106][107][108][109][110] are cited in the Supplementary Material.…”

“…The supporting information can be downloaded at: . References [ 97 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 ] are cited in the Supplementary Material.…”