biostudies-literatureJeong SAjou UniversityMinistry of Health & Welfare, Republic of KoreaNational Research Foundation of Korea, Korea GovernmentNational Research Council of Science & Technology, Korea Governmente2415626https://www.ebi.ac.uk/biostudies/studies/S-EPMC12097015biostudies-literatureUnknown12(19)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, Advanced science (Weinheim, Baden-Wurttemberg, Germany)Development of MDM2-Targeting PROTAC for Advancing Bone Regeneration.PMC12097015HI22C1609RS-2024-00347988CAP23011-101Ahmed WHong KTLee SKim JMKim SYAn SCLee JKim JChoi JKim MChoi SLee JSAn HJChoi WYoo THJeong SCha JKfalseDevelopment of MDM2-Targeting PROTAC for Advancing Bone Regeneration.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, 2025-01-01T00:00:00Z2025 May2026-06-01T19:15:23.976Z2026-05-21T03:08:47.361ZS-EPMC120970154012564610.1002/advs.202415626