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 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.

Keywords:

• Synthesis
• triazine
• hydrazine
• IDH2
• enasidenib
• leukaemia
• anticancer

Acknowledgements

The authors wish to thank the management of Faculty of Pharmacy, Tanta University for providing infrastructure facilities to carry out this research work.

Disclosure statement

The authors declare no competing financial interest.

Additional information

Funding

This work was supported by the Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University, Saudi Arabia [GRANT1,645].