Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK).
Kong X, Pan P, Sun H, Xia H, Wang X, Li Y, Hou T.
As a receptor tyrosine kinase of insulin receptor (IR) subfamily, anaplastic lymphoma kinase (ALK) has been validated to play important roles in various cancers, especially anaplastic large cell lymphoma (ALCL), nonsmall cell lung cancer (NSCLC), and neuroblastomas. Currently, five small-molecule inhibitors of ALK, including Crizotinib, Ceritinib, Alectinib, Brigatinib, and Lorlatinib, have been approved by the U.S. Food and Drug Administration (FDA) against ALK-positive NSCLCs. Novel type-I<sup>1</sup>/<sub>2</sub> and type-II ALK inhibitors with improved kinase selectivity and enhanced capability to combat drug resistance have also been reported. Moreover, the 'proteolysis targeting chimera' (PROTAC) technique has been successfully applied in developing ALK degraders, which opened a new avenue for targeted ALK therapies. This review provides an overview of the physiological and biological functions of ALK, the discovery and development of drugs targeting ALK by focusing on their chemotypes, activity, selectivity, and resistance as well as potential therapeutic strategies to overcome drug resistance.