Title:Multi-Kinase Inhibitors
VOLUME: 22 ISSUE: 6
Author(s):Laura Garuti, Marinella Roberti and Giovanni Bottegoni
Affiliation:Department of Pharmacy and Biotechnology, University of Bologna, via Belmeloro 6, I-40126 Bologna, Italy.
Keywords:ATP-competitive, biological activity, heterocycles, inhibition, irreversible inhibitors, kinase, multi-target, SAR.
Abstract: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.
