Rational design of resorcylic acid lactone analogues as covalent MNK1/2 kinase inhibitors by tuning the reactivity of an enamide Michael acceptor

Rational design of resorcylic acid lactone analogues as covalent MNK1/2 kinase inhibitors by tuning the reactivity of an enamide Michael acceptor
Title:
Rational design of resorcylic acid lactone analogues as covalent MNK1/2 kinase inhibitors by tuning the reactivity of an enamide Michael acceptor
Other Titles:
ChemMedChem
Keywords:
Publication Date:
08 August 2013
Citation:
Xu, J.; Chen, A. Q.; Joy, J.; Xavier, V. J.; Ong, E. H. Q.; Hill, J.; Chai, C. L. L., Rational design of resorcylic acid lactone analogues as covalent MNK1/2 kinase inhibitors by tuning the reactivity of an enamide Michael acceptor. ChemMedChem 2013, 8, (9), p 1483-1494.
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.
License type:
PublisherCopyrights
Funding Info:
This work was funded by the Agency for Science, Technology and Research (A*STAR), Singapore.
Description:
This is the peer reviewed version of the following article: Xu, J.; Chen, A. Q.; Joy, J.; Xavier, V. J.; Ong, E. H. Q.; Hill, J.; Chai, C. L. L., Rational design of resorcylic acid lactone analogues as covalent MNK1/2 kinase inhibitors by tuning the reactivity of an enamide Michael acceptor. ChemMedChem 2013, 8, (9), p 1483-1494, which has been published in final form at http://dx.doi.org/10.1002/cmdc.201300231. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
ISSN:
1860-7179
1860-7187
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