CHAPTER 17: Allosteric Inhibition of Abl Kinase

Ever since when the mechanism of allosteric regulation was postulated for the first time in 1965 by Monod, Wyman and Changeux, fifty 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 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 the following chapter an in depth description of one of the most studied allosteric modulation mechanism will be provided. c-Abl protein kinase represents a noteworthy example of how a small post-traductional modification (myristoylation of the N-terminal region in the protein sequence) can drive a complex mechanism of domains’ rearrangements, determining the activation state of the enzyme. Many efforts have been devoted from scientists all around the world in studying the molecular basis for the autoinhibition mechanism of c-Abl, and its derived oncogenic protein Bcr-Abl, leading to the identification of the first allosteric inhibitor GNF-5 actually involved in a Phase I clinical trial for the treatment of Chronic Myelogenous Leukemia (CML).