Please use this identifier to cite or link to this item: https://doi.org/10.1002/cmdc.201300231
Title: Rational design of resorcylic acid lactone analogues as covalent MNK1/2 kinase inhibitors by tuning the reactivity of an enamide Michael acceptor
Authors: Xu, J.
Chen, A.
Joy, J.
Xavier, V.J.
Ong, E.H.Q.
Hill, J.
Chai, C.L.L. 
Keywords: Antitumor agents
Covalent inhibitors
Enamides
Kinases
Michael acceptors
Resorcylic acid lactones
Issue Date: Sep-2013
Citation: Xu, J., Chen, A., Joy, J., Xavier, V.J., Ong, E.H.Q., Hill, J., Chai, C.L.L. (2013-09). Rational design of resorcylic acid lactone analogues as covalent MNK1/2 kinase inhibitors by tuning the reactivity of an enamide Michael acceptor. ChemMedChem 8 (9) : 1483-1494. ScholarBank@NUS Repository. https://doi.org/10.1002/cmdc.201300231
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 1HNMR 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. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Source Title: ChemMedChem
URI: http://scholarbank.nus.edu.sg/handle/10635/106292
ISSN: 18607179
DOI: 10.1002/cmdc.201300231
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