Proteolysis-targeting chimeras (PROTACs) degrade target proteins through the ubiquitin-proteasome system. To date, PROTACs are primarily used to treat various diseases; however, they have not been applied in regenerative therapy. Herein, this work introduces MDM2-targeting PROTACs customized for application in bone regeneration. An MDM2-PROTAC library is constructed by combining Nutlin-3 and CRBN ligands with various linker designs. Through a multistep validation process, this work develops MDM2-PROTACs (CL144 and CL174) that presented potent degradation efficiency and a robust inductive effect on the biomineralization. Next, this work performs whole-transcriptome analysis to dissect the biological effects of the CL144, and reveals the upregulation of osteogenic marker genes. Furthermore, CL144 effectively induced bone regeneration in bone graft and ovariectomy (OVX) models after local and systemic administration, respectively. In the OVX model, the combination treatment with CL144 and alendronate induced a synergistic effect. Overall, this study demonstrates the promising role of MDM2-PROTAC in promoting bone regeneration, marking the first step toward expanding the application of the PROTAC technology.
The authors are grateful to S.Y.P. for discussion during the manuscript preparation. The authors also thank the Dental Research Institute for providing access to research facilities and equipment. This work is supported by Ministry of Health & Welfare, Republic of Korea (grant number: HI22C1609, JMK), the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. RS\u20102024\u201000347988, JC), the National Research Council of Science & Technology (NST) grant by the Korea government (MSIT) (No. CAP23011\u2010101, JC), the Ajou University research fund (JC).
