Development of dual aptamers-functionalized c-MET PROTAC degraders for targeted therapy of osteosarcoma

Osteosarcoma (OS) is the most common bone malignancy. c-MET is recognized as a therapeutic target. However, traditional c-MET inhibitors show compromised efficacy due to the acquired resistance and side effects. PROTACs targeting c-MET have displayed improved antitumor efficacy by overcoming drug resistance, whereas safety concern caused by lack of tumor-targeting ability is still a pending issue. AS1411 is an aptamer that recognizes and penetrates tumors by targeting nucleolin (NCL) overexpressed on the surface of tumor cells. Since NCL interacts with an E3 ligase MDM2 intracellularly, we repurposed AS1411 as an MDM2 recruiter by employing NCL as a bridge.