Small Molecule Inhibitor Design for Anaplastic Lymphoma Kinase Inhibition

The Anaplastic Lymphoma Kinase (ALK) gene has been linked to tumorigenesis in a number of human cancers, including anaplastic large cell lymphoma (ALCL) and neuroblastoma. While ALK mutations in ALCL and many other cancers occur as a result of gene fusions with wild type kinase domains, those in neuroblastoma stem from single nucleotide polymorphisms (SNPs) in the kinase domain. These lead to autophosphorylation and constitutive signaling by ALK for cell growth and division, ultimately causing cancer. Crizotinib, an ATP-competitive ALK inhibitor, has proven to be an effective inhibitor of both ALKWT and ALKMutant kinase domains, and is in the middle of clinical trials for neuroblastoma treatment. This review used the PyMOL and AutoDock Vina computational biology programs to predict the binding affinities of Crizotinib, Ceritinib (LDK378), and PF-922 to three different ALK kinase mutations in order to determine the most effective inhibitor. The EGFR inhibitors gefitinib and erlotinib were also analyzed in complex with ALK as negative controls to verify the specificity of the ALK inhibitors. The crystalline complexes were then qualitatively analyzed to uncover the mechanics behind the docking results. Based on the results generated by Vina, PF-922, representative of the second generation of ALK inhibitors, is predicted to be the most effective out of the tested compounds. These results may be used to predict the inhibitor that will require the lowest dosage to achieve the greatest inhibitory effect, hopefully leading to fewer side effects from treatment