Structural Studies on the Anaplastic Lymphoma Kinase

The ALK tyrosine kinase is expressed, as NMP/ALK fusion protein, in approximately 60% of Anaplastic Large Cell Lymphoma (ALCL) cases and in other cancers such as Non Small Cell Lung Cancer (NSCLC) and neuroblastoma. ALK kinase domain constitutive activation is responsible for the malignant transformation. Structural characterization of the ALK kinase domain and information about drug-protein interactions could be very useful in the rational design of new specific drugs for treatment of the ALK+ ALCL and other ALK+ tumours. This work has been focused on the production and purification of different forms of the ALK kinase domain to obtain good candidates for ALK structural studies by X-ray crystallography and STD-NMR. The best recombinant protein form has been used to screen potential ALK inhibitors and to demonstrate the interaction between the ALK kinase domain and a new kinase inhibitor. The results of this work could pave the way to the development of new specific drugs for treatment of ALK+ diseases. This work could provide a methodological model for recombinant proteins production and purification and for next drug-protein interaction studies.