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A miniaturized PROTAC named AP-1 with potent activity and high selectivity was discovered by researchers, which greatly reduces the length of linker compared with regular PROTAC. The AP-1 showed strong ALK-degrading activity in ALK-dependent cell lines, and displayed better safety and selectivity than traditional small-molecule inhibitors in ALK-independent cell lines. [Display omitted] • Proteolysis-targeting chimera (PROTAC) for protein degradation can effectively inhibit tumor growth and has the potential to reduce drug resistance. • PROTAC showed better activity than small-molecule inhibitors against mutable proteins and proteins with excessive fusion expression forms. • The miniaturized PROTAC designed by simplest principle can effectively reduce the molecular weight of traditional PROTAC, improve the activity and make up for the deficiency. • The use of ultra-short-linker reduced the overall molecular weight without affecting the activity of PROTAC molecules, resulting in excellent in vivo and in vitro antitumor effects. The approved small-molecule inhibitors of anaplastic lymphoma kinase (ALK) have shown remarkable efficacy in some subset of cancer patients. However, the numerous ALK mutants or fusion partners are resistant to such drugs, greatly limiting their application in clinic. Despite the drug design strategy of proteolysis-targeting chimera (PROTAC) holds great potential to overcome drug resistance in theory, there are obvious disadvantages for the reported PROTACs that include high molecular weight, long linkers, difficult synthesis routes as well as insufficient evidence in activity for diverse ALK mutants. In this study, we designed and synthesized a miniaturized PROTAC of ALK named AP-1 following the principle of minimalist design. Two simple chemical units of ligands and a minimized linker with only two atoms were selected for synthesis of AP-1. At cellular level, AP-1 successfully degraded three types of ALK mutants including NPM-ALK, EML4-ALK and F1174L mutation ALK form with potent activity, high selectivity in ALK-positive cells. In xenograft mouse model, AP-1 showed the stronger antitumor efficacy than ceritinib as well as ALK degraders reported in literatures. AP-1 with an extremely simple PROTAC structure can be served as an effective candidate drug for therapy of various types of ALK-positive cancers. And the design principle of AP-1 has a good guiding significance for overcoming the disadvantages such as excessive molecular weight and poor solubility of PROTAC. [ABSTRACT FROM AUTHOR]