Laura Garuti, Marinella Roberti and Giovanni Bottegoni Pages 695 - 712 ( 18 )
The limitations of many mono-kinase inhibitors can be overcome by agents with multi-target action. An important advantage of targeting more than one kinase, is an increase in potency, due to the synergistic effect. Moreover, this approach can reduce the possibility of developing drug resistance. Several multitarget agents have been designed as single kinase inhibitors and found to be multi-target inhibitors because of the structural homology among the ATP-binding site of kinases. In other cases, these inhibitors have been obtained by optimization of potent individual inhibitors or by combination of selective ligands. Also some irreversible inhibitors act on different kinases and covalently modify the cysteine residues located near the ATP-binding pocket. In this review the most recent examples of multi-kinase inhibitors are reported, focusing on chemical structures, structure-activity relationship (SAR) and biological activity. These inhibitors, suitably substituted, could be used in designing other multitarget agents. Virtual molecular docking would suggest potential targets of molecules, moreover combining pharmacophore combination and screening methods could probably help in the discovery of more potent multikinase inhibitors.
ATP-competitive, biological activity, heterocycles, inhibition, irreversible inhibitors, kinase, multi-target, SAR.
Department of Pharmacy and Biotechnology, University of Bologna, via Belmeloro 6, I-40126 Bologna, Italy.