Rational design of resorcylic acid lactone analogues as covalent MNK1/2 kinase inhibitors by tuning the reactivity of an enamide Michael acceptor.
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.
Institute of Chemical and Engineering Sciences-ICES, Agency for Science, Technology and Research-A*STAR, 8 Biomedical Grove, Neuros #07-01, Singapore 138665, Singapore.
Jin
J
Xu
Anqi
A
Chen
Joma
J
Joy
Vanessa Joanne
VJ
Xavier
Esther H Q
EH
Ong
Jeffrey
J
Hill
Christina L L
CL
Chai
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007536:Isomerism; D007700:Kinetics; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012118:Resorcinols / Q000737:chemistry / Q000633:toxicity
D000577:Amides; D047908:Intracellular Signaling Peptides and Proteins; C405053:L 783277; D007783:Lactones; D047428:Protein Kinase Inhibitors; D012118:Resorcinols; C491395:MKNK1 protein, human; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases
Michael acceptors; antitumor agents; covalent inhibitors; enamides; kinases; resorcylic acid lactones