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Discovery of 5-(2-(Phenylamino)pyrimidin-4-yl)thiazol-2(3H)-one Derivatives as Potent Mnk2 Inhibitors: Synthesis, SAR Analysis and Biological Evaluation

Authors

  • Sarah Diab,

    1. Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001 (Australia)
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  • Theodosia Teo,

    1. Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001 (Australia)
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  • Dr. Malika Kumarasiri,

    1. Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001 (Australia)
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  • Dr. Peng Li,

    1. Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001 (Australia)
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  • Dr. Mingfeng Yu,

    1. Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001 (Australia)
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  • Dr. Frankie Lam,

    1. Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001 (Australia)
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  • Sunita K. C. Basnet,

    1. Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001 (Australia)
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  • Dr. Matthew J. Sykes,

    1. Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001 (Australia)
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  • Dr. Hugo Albrecht,

    1. Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001 (Australia)
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  • Dr. Robert Milne,

    1. Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001 (Australia)
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  • Prof. Shudong Wang

    Corresponding author
    1. Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001 (Australia)
    • Centre for Drug Discovery and Development, Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001 (Australia)

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Abstract

Phosphorylation of eIF4E by human mitogen-activated protein kinase (MAPK)-interacting kinases (Mnks) is crucial for human tumourigenesis and development. Targeting Mnks may provide a novel anticancer therapeutic strategy. However, the lack of selective Mnk inhibitors has so far hampered pharmacological target validation and clinical drug development. Herein, we report, for the first time, the discovery of a series of 5-(2-(phenylamino)pyrimidin-4-yl)thiazole-2(3H)-one derivatives as Mnk inhibitors. Several derivatives demonstrate very potent Mnk2 inhibitory activity. The most active and selective compounds were tested against a panel of cancer cell lines, and the results confirm the cell-type-specific effect of these Mnk inhibitors. Detailed cellular mechanistic studies reveal that Mnk inhibitors are capable of reducing the expression level of anti-apoptotic protein Mcl-1, and of promoting apoptosis in MV4-11 acute myeloid leukaemia cells.

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