Development of Novel Inhibitors for ALK Mutant for Non-Small Cell Lung Cancer

Dysregulation of anaplastic lymphoma kinase (ALK) has been detected in nonsmall cell lung cancer (NSCLC) in the form of EML4-ALK fusion. Secondary mutations opposing activity of the first generation ALK inhibitor crizotinib came into existence, requiring mutation-targeting drug discovery for the powerful second-line treatment. In this study, we report 4-phenoxyquinoline-based inhibitors that overcome crizotinib resistance to ALK L1196M, discovered by the fragment-growing strategy. The inhibitors exhibited significant antiproliferative effects on H2228 CR crizotinib-resistant cells as well as nonsmall cell lung cancer cells compared to crizotinib. As expected, crizotinib significantly inhibited proliferation in H2228 crizotinib-sensitive cells (IC₅₀ = 2.5 μM) but did not effectively inhibit cell proliferation of H2228 CR crizotinib-resistant cells (IC₅₀ = 10 μM). To investigate whether new inhibitors could overcome the resistance to crizotinib, H2228 CR cells were treated with them. The results from the MTT assay indicated that H2228 CR cells exhibited high resistance to crizotinib, whereas they effectively inhibited the cell growth of H2228 CR cells in a dose-dependent manner. In the study to identify the molecular mechanism, they decreased the expression of PI3K/AKT and MAPK signaling pathways. These new inhibitors would be promising candidates for the L1196M mutant of ALK for non-small cell lung cancer.