Discovery of n-phenyl-4-(1h-pyrrol-3-yl)pyrimidin-2-amine derivatives as potent mnk2 inhibitors: design, synthesis, sar analysis, and evaluation of in vitro anti-leukaemic activity
Date
2019
Authors
Abdelaziz, A.M.
Diab, S.
Islam, S.
KC Basnet, S.
Noll, B.
Li, P.
Mekonnen, L.B.
Lu, J.
Albrecht, H.
Milne, R.W.
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Journal article
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Medicinal Chemistry, 2019; 15(6):600-621
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Abstract
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 of cancer. 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 N-phenyl-4-(1H-pyrrol-3-yl)pyrimidin-2-amine would offer potent and selective Mnk inhibitors.
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Copyright 2019 Bentham Science Publishers