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

• Published in: ChemMedChem 2013-09, Vol.8 (9), p.1483-1494
• Main Authors: Xu, Jin, Chen, Anqi, Joy, Joma, Xavier, Vanessa Joanne, Ong, Esther H. Q., Hill, Jeffrey, Chai, Christina L. L.
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - toxicity; antitumor agents; Binding sites; Cell Line, Tumor; Cell Survival - drug effects; covalent inhibitors; Crystallography, X-Ray; Drug Design; enamides; HeLa Cells; Humans; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - metabolism; Isomerism; Kinases; Kinetics; Lactones - chemical synthesis; Lactones - chemistry; Lactones - toxicity; Michael acceptors; Protein Binding; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - toxicity; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Resorcinols - chemistry; Resorcinols - toxicity; resorcylic acid lactones
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201300231

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. Reactivity‐tunable Michael acceptor: Enamide analogues of resorcylic acid lactone (RAL) as novel covalent inhibitors of MNK1/2 kinases were developed in this study. The covalent binding ability of such enamides can be tuned by attaching an electron‐withdrawing motif to enhance its reactivity toward the cysteine residues at the MNK1/2 binding sites.