Type II Kinase Inhibitors: An Opportunity in Cancer for Rational Design

Javier      Blanc; Raphael      Geney; Christel      Menet

Abstract

With the advent of the Type II kinase inhibitor imatinib (Gleevec) for treatment against cancer, rational design of tailored molecules has brought a revolution in medicinal chemistry for treating tumours caused by kinase malfunctioning. Among different types of kinase inhibitors, the design of Type II inhibitors has been rationalized for maximizing the benefits and reducing drawbacks. Here we highlight the development made in Type II inhibitors, discussing the advantages and disadvantages of these types of molecules. Furthermore, we present the strategies for designing druggable molecules that either selectively inhibit target kinases or overcome drug resistance.

Keywords: Allosteric inhibitors, cancer, covalent inhibitors, DFG-in, DFG-out, kinase inhibitors, Type I inhibitors, Type II inhibitors, Type III inhibitors, Type IV inhibitors.