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

Rationale: 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. Methods: We select the ssDNA c-MET aptamer SL1 as the c-MET ligand to design dual aptamer-functionalized PROTACs, as SL1 can be easily conjugated to AS1411 through base-pair complementarity using a nucleic acid linker. Four AS1411-SL1 chimeras are generated by linking AS1411 to either the 5' or 3' terminus of SL1 via two different lengths of nucleic acid linkers. The therapeutic efficacy of these PROTACs is evaluated through both in vitro and in vivo experiments. Results: The PROTACs enable the ubiquitination and degradation of c-MET. The PROTACs effectively inhibit growth, enhance Apoptosis, and overcome drug resistance of OS cells in vitro. The PROTACs demonstrate in vivo tumor-targeting ability and facilitate the OS treatment with no detectable toxicity. Conclusion: This study suggests that the AS1411-SL1 chimeras could be promising c-MET degraders for targeted therapy of OS.

AS1411; PROTAC; c-MET; nucleolin; osteosarcoma.