CHAPTER 17: Allosteric Inhibition of Abl Kinase Check Access

Since the mechanism of allosteric regulation was postulated for the first time in 1965 by Monod, Wyman and Changeux, 50 years have passed. From that moment our vision and understanding of the ligand–protein interaction process have been completely changed. Proteins started to be considered to be not fixed biological entities but flexible structures endowed with an activity which could be finely tuned by interaction with other proteins or new small molecules able to bind pockets different from the catalytic sites. In this chapter an in-depth description of one of the most studied allosteric modulation mechanisms will be provided. Abelson murine-leukemia viral-oncogene homolog-1 (c-Abl) protein kinase represents a noteworthy example of how a small post-translational modification (myristoylation of the N-terminal region of the protein sequence) can drive a mechanism of complex domain rearrangements, determining the activation state of the enzyme. Many efforts have been devoted, by scientists all around the world, to studying the molecular basis for the autoinhibition mechanism of c-Abl, and its derived oncogenic fusion protein breakpoint cluster region–Abl (Bcr–Abl), leading to the identification of the first allosteric inhibitor GNF-5, currently undergoing a Phase I clinical trial for the treatment of chronic myelogenous leukemia (CML).