Rational Design of Resorcylic Acid Lactone Analogues as Covalent MNK1/2 Kinase Inhibitors by Tuning the Reactivity of an Enamide Michael Acceptor

Authors

  • Jin Xu,

    1. Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 8 Biomedical Grove, Neuros #07-01, Singapore 138665 (Singapore)
    2. Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543 (Singapore)
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  • Dr. Anqi Chen,

    Corresponding author
    1. Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 8 Biomedical Grove, Neuros #07-01, Singapore 138665 (Singapore)
    • Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 8 Biomedical Grove, Neuros #07-01, Singapore 138665 (Singapore)

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  • Dr. Joma Joy,

    1. Protein Biochemistry Enzymology, Experimental Therapeutic Centre (ETC), Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos Level 3, Singapore 13866 (Singapore)
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  • Vanessa Joanne Xavier,

    1. Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 8 Biomedical Grove, Neuros #07-01, Singapore 138665 (Singapore)
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  • Esther H. Q. Ong,

    1. Protein Biochemistry Enzymology, Experimental Therapeutic Centre (ETC), Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos Level 3, Singapore 13866 (Singapore)
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  • Dr. Jeffrey Hill,

    1. Protein Biochemistry Enzymology, Experimental Therapeutic Centre (ETC), Agency for Science, Technology and Research (A*STAR), 31 Biopolis Way, Nanos Level 3, Singapore 13866 (Singapore)
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  • Prof. Christina L. L. Chai

    Corresponding author
    1. Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 8 Biomedical Grove, Neuros #07-01, Singapore 138665 (Singapore)
    2. Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543 (Singapore)
    • Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 8 Biomedical Grove, Neuros #07-01, Singapore 138665 (Singapore)

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Abstract

Recent biological and computational advances in drug design have led to renewed interest in targeted covalent inhibition as an efficient and practical approach for the development of new drugs. As part of our continuing efforts in the exploration of the therapeutic potential of resorcylic acid lactones (RALs), we report herein the design, synthesis, and biological evaluation of conveniently accessible RAL enamide analogues as novel covalent inhibitors of MAP kinase interacting kinases (MNKs). In this study, we have successfully demonstrated that the covalent binding ability of RAL enamides can be tuned by attaching an electron-withdrawing motif, such as an acyl group, to enhance its reactivity toward the cysteine residues at the MNK1/2 binding sites. We have also shown that 1H NMR spectroscopy is a convenient and effective tool for screening the covalent binding activities of enamides using cysteamine as a mimic of the key cysteine residue in the enzyme, whereas mass spectrometric analysis confirms covalent modification of the kinases. Preliminary optimization of the initial hit led to the discovery of enamides with low micromolar activity in MNK assays. Cancer cell line assays have identified RAL enamides that inhibit the growth of cancer cells with similar potency to the natural product L-783,277.

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