Discovery of Novel Kinase Inhibitors Belonging to Isosteric N-Acylhydrazone or N-Sulfonylhydrazone Classes
The growing impact of inflammatory chronic-degenerative diseases able to affecting different tissues/organs such as the articulations (e.g. rheumatoid arthritis), the bowel (e.g. Chron’s disease), the blood vessels (e.g. pulmonary hypertension, cerebral cavernous malformation), the metabolic behavior (e.g. diabetes mellitus) and also different types of cancer has led to the emerging necessity of discovering novel drug candidates useful to treating these multifactorial diseases. Since the complete characterization of the human genome, the protein kinases were identified as one of the main group of druggable enzymes. However, a number relatively reduced of kinases has been still exploited as drug targets. This kind of proteins play a central role in signal transduction, being related to other important processes like the control of cell cycle, proliferation, differentiation, mobility and mechanisms related to survival or cell death. Many of these processes regulated by kinases actions are related to the pathogenesis of chronic multifactorial diseases. In our research group, i.e. LASSBio-UFRJ, we have successfully exploited the N-acylhydrazone1 (NAH) framework as a privileged structure2 to the identification of compounds able to be selectively recognized by different biotargets, such as adenosine A2A receptors, PDE-4 and HDAC6 enzymes, among others. This peptidomimetic framework, which is resultant from the fusion between amide and imine subunits, is able to provide points of interaction with a wide range of amino acid residues, comprising both H-bond acceptor and donor sites. So, this lecture describes our efforts to found out novel inhibitors of some serine-threonine kinases, such as IKKb, p38, ROCK and GSK-3b, and tyrosine kinases (PI3Ka) belonging to N-acylhydrazone or isosteric N-sulfonylhydrazone classes applying different strategies of molecular modification.3-6
Thanks are due to INCT-INOFAR (BR), CNPq (BR), CAPES (BR), DECIT-MS (BR) and also to FAPERJ (BR) for the financial support and fellowships.
1 Thota, S. et al. (2018) Bioorg. Med. Chem. Lett., 28, 2797; 2Duarte, C. D. et al. (2007) Mini Rev. Med. Chem., 7, 1108; 3 Avila, C. M. (2011) Eur. J. Med. Chem., 46, 1245; 4 Guedes, I. A. et al. (2015) ChemMedChem, 11, 234; 5Oliveira, R. G et al. (2018) J. Enz. Inhib. Med. Chem., 33, 1181; 6 Tesch, R. et al. (2018) Angew. Chem. Int. Ed., 57, 9970.