Background: Aberrant expression of eukaryotic translation initiation factor 4E (eIF4E)
is common in many types of cancer including acute myeloid leukaemia (AML). Phosphorylation
of eIF4E by MAPK-interacting kinases (Mnks) is essential for the eIF4E-mediated oncogenic activity.
As such, the pharmacological inhibition of Mnks can be an effective strategy for the treatment
Methods: A series of N-phenyl-4-(1H-pyrrol-3-yl)pyrimidin-2-amine derivatives was designed and
synthesised. The Mnk inhibitory activity of these derivatives as well as their anti-proliferative activity
against MV4-11 AML cells was determined.
Results: These compounds were identified as potent Mnk2 inhibitors. Most of them demonstrated
potent anti-proliferative activity against MV4-11 AML cells. The cellular mechanistic studies of
the representative inhibitors revealed that they reduced the level of phosphorylated eIF4E and induced
apoptosis by down-regulating the anti-apoptotic protein myeloid cell leukaemia 1 (Mcl-1)
and by cleaving poly(ADP-ribose)polymerase (PARP). The lead compound 7k possessed desirable
pharmacokinetic properties and oral bioavailability.
Conclusion: This work proposes that exploration of the structural diversity in the context of Nphenyl-
4-(1H-pyrrol-3-yl)pyrimidin-2-amine would offer potent and selective Mnk inhibitors.