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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

Author(s):

Ahmed M. Abdelaziz, Sarah Diab, Saiful Islam, Sunita K. C. Basnet, Ben Noll, Peng Li, Laychiluh B. Mekonnen, Jingfeng Lu, Hugo Albrecht, Robert W. Milne, Cobus Gerber, Mingfeng Yu * and Shudong Wang*   Pages 1 - 21 ( 21 )

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 Nphenyl- 4-(1H-pyrrol-3-yl)pyrimidin-2-amine would offer potent and selective Mnk inhibitors.

Keywords:

Mnk, eIF4E, Inhibitor, Structure-activity relationship, N-Phenyl-4-(1H-pyrrol-3-yl)pyrimidin-2-amine, Anti-leukaemia.

Affiliation:

Centre for Drug Discovery and Development, Cancer Research Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Centre for Drug Discovery and Development, Cancer Research Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Centre for Drug Discovery and Development, Cancer Research Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Centre for Drug Discovery and Development, Cancer Research Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Centre for Drug Discovery and Development, Cancer Research Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Centre for Drug Discovery and Development, Cancer Research Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Centre for Drug Discovery and Development, Cancer Research Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Centre for Drug Discovery and Development, Cancer Research Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Centre for Drug Discovery and Development, Cancer Research Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Centre for Drug Discovery and Development, Cancer Research Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Centre for Drug Discovery and Development, Cancer Research Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Centre for Drug Discovery and Development, Cancer Research Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001, Centre for Drug Discovery and Development, Cancer Research Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5001



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