Design of novel ALK inhibitors

Oncological diseases are one of the leading causes of mortality in all countries of the world. Every year in Russia, lung cancer (LC) is diagnosed in more than 60 thousand people (47 thousand men and 13 thousand women). These epidemiological data explain the high interest in prevention, early diagnosis and development of new methods of drug therapy for RL. To date, a number of drugs are available for the treatment of NSCLC, a significant proportion of which are small drug molecules. More than 100 targeted drugs are being investigated at various stages of clinical trials, with a much larger number in early stages of development, including preclinical trials. Despite the relatively large number of ALK inhibitors on the market, drug resistance remains a major challenge. To develop novel second-generation ALK inhibitors, computational modelling using molecular docking was performed and showed that crizotinib was able to bind to both ALK (WT) and ALK (L1196M) with comparable affinity, which did not correlate with published experimental data. Differences in the apo- and holo-forms of ALK (L1196M) were identified, which presumably influence the binding of crizotinib to the above variants. Replacement of the central fragment (2-aminopyrimidine) in the crizotinib structure with a larger scaffold while maintaining binding to key Met1199 (hinge region), which prevents conformational rearrangement of Met1196 in the apo-form of ALK (L1196M), was selected as a possible strategy to enhance activity against the mutant form. Using a scaffold hopping approach and molecular docking, new analogues of crizotinib with potentially better activity against ALK (L1196M) were proposed. Retrosynthetic analysis was performed for the three most promising structures and the results predict that two compounds out of three have relatively high synthetic availability.