Development of MDM2‐Targeting PROTAC for Advancing Bone Regeneration
Abstract 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 customize...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-05-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202415626 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850270292784447488 |
|---|---|
| author | Sol Jeong Jae‐Kook Cha Wasim Ahmed Jaewan Kim Minsup Kim Kyung Tae Hong Wonji Choi Sunjoo Choi Tae Hyeon Yoo Hyun‑Ju An Seung Chan An Jaemin Lee Jimin Choi Sun‐Young Kim Jun‐Seok Lee Soonchul Lee Junwon Choi Jin Man Kim |
| author_facet | Sol Jeong Jae‐Kook Cha Wasim Ahmed Jaewan Kim Minsup Kim Kyung Tae Hong Wonji Choi Sunjoo Choi Tae Hyeon Yoo Hyun‑Ju An Seung Chan An Jaemin Lee Jimin Choi Sun‐Young Kim Jun‐Seok Lee Soonchul Lee Junwon Choi Jin Man Kim |
| author_sort | Sol Jeong |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-db6b5ee5eb3c4c0b8e8cc4f656dd2daa |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-db6b5ee5eb3c4c0b8e8cc4f656dd2daa2025-08-20T01:52:42ZengWileyAdvanced Science2198-38442025-05-011219n/an/a10.1002/advs.202415626Development of MDM2‐Targeting PROTAC for Advancing Bone RegenerationSol Jeong0Jae‐Kook Cha1Wasim Ahmed2Jaewan Kim3Minsup Kim4Kyung Tae Hong5Wonji Choi6Sunjoo Choi7Tae Hyeon Yoo8Hyun‑Ju An9Seung Chan An10Jaemin Lee11Jimin Choi12Sun‐Young Kim13Jun‐Seok Lee14Soonchul Lee15Junwon Choi16Jin Man Kim17Department of Oral Microbiology and Immunology School of Dentistry and Dental Research Institute Seoul National University Seoul 08826 Republic of KoreaDepartment of Periodontology Research Institute of Periodontal Regeneration College of Dentistry Yonsei University Seoul 03722 Republic of KoreaDepartment of Molecular Science and Technology Ajou University Gyeonggi‐do 16499 Republic of KoreaDepartment of Molecular Science and Technology Ajou University Gyeonggi‐do 16499 Republic of KoreaTARS Scientific Seoul 01717 Republic of KoreaDepartment of Pharmacology Korea University College of Medicine Korea University Seoul 02841 Republic of KoreaDepartment of Molecular Science and Technology Ajou University Gyeonggi‐do 16499 Republic of KoreaDepartment of Molecular Science and Technology Ajou University Gyeonggi‐do 16499 Republic of KoreaDepartment of Molecular Science and Technology Ajou University Gyeonggi‐do 16499 Republic of KoreaDepartment of Orthopaedic Surgery CHA Bundang Medical Center CHA University School of Medicine Gyeonggi‐do 13488 Republic of KoreaDepartment of Orthopaedic Surgery CHA Bundang Medical Center CHA University School of Medicine Gyeonggi‐do 13488 Republic of KoreaDepartment of Orthopaedic Surgery CHA Bundang Medical Center CHA University School of Medicine Gyeonggi‐do 13488 Republic of KoreaDepartment of Periodontology Research Institute of Periodontal Regeneration College of Dentistry Yonsei University Seoul 03722 Republic of KoreaDepartment of Conservative Dentistry and Dental Research Institute School of Dentistry Seoul National University Seoul 08826 Republic of KoreaDepartment of Pharmacology Korea University College of Medicine Korea University Seoul 02841 Republic of KoreaDepartment of Orthopaedic Surgery CHA Bundang Medical Center CHA University School of Medicine Gyeonggi‐do 13488 Republic of KoreaDepartment of Molecular Science and Technology Ajou University Gyeonggi‐do 16499 Republic of KoreaDepartment of Oral Microbiology and Immunology School of Dentistry and Dental Research Institute Seoul National University Seoul 08826 Republic of KoreaAbstract 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.https://doi.org/10.1002/advs.202415626boneMDM2osteoporosisPROTACregenerative medicine |
| spellingShingle | Sol Jeong Jae‐Kook Cha Wasim Ahmed Jaewan Kim Minsup Kim Kyung Tae Hong Wonji Choi Sunjoo Choi Tae Hyeon Yoo Hyun‑Ju An Seung Chan An Jaemin Lee Jimin Choi Sun‐Young Kim Jun‐Seok Lee Soonchul Lee Junwon Choi Jin Man Kim Development of MDM2‐Targeting PROTAC for Advancing Bone Regeneration Advanced Science bone MDM2 osteoporosis PROTAC regenerative medicine |
| title | Development of MDM2‐Targeting PROTAC for Advancing Bone Regeneration |
| title_full | Development of MDM2‐Targeting PROTAC for Advancing Bone Regeneration |
| title_fullStr | Development of MDM2‐Targeting PROTAC for Advancing Bone Regeneration |
| title_full_unstemmed | Development of MDM2‐Targeting PROTAC for Advancing Bone Regeneration |
| title_short | Development of MDM2‐Targeting PROTAC for Advancing Bone Regeneration |
| title_sort | development of mdm2 targeting protac for advancing bone regeneration |
| topic | bone MDM2 osteoporosis PROTAC regenerative medicine |
| url | https://doi.org/10.1002/advs.202415626 |
| work_keys_str_mv | AT soljeong developmentofmdm2targetingprotacforadvancingboneregeneration AT jaekookcha developmentofmdm2targetingprotacforadvancingboneregeneration AT wasimahmed developmentofmdm2targetingprotacforadvancingboneregeneration AT jaewankim developmentofmdm2targetingprotacforadvancingboneregeneration AT minsupkim developmentofmdm2targetingprotacforadvancingboneregeneration AT kyungtaehong developmentofmdm2targetingprotacforadvancingboneregeneration AT wonjichoi developmentofmdm2targetingprotacforadvancingboneregeneration AT sunjoochoi developmentofmdm2targetingprotacforadvancingboneregeneration AT taehyeonyoo developmentofmdm2targetingprotacforadvancingboneregeneration AT hyunjuan developmentofmdm2targetingprotacforadvancingboneregeneration AT seungchanan developmentofmdm2targetingprotacforadvancingboneregeneration AT jaeminlee developmentofmdm2targetingprotacforadvancingboneregeneration AT jiminchoi developmentofmdm2targetingprotacforadvancingboneregeneration AT sunyoungkim developmentofmdm2targetingprotacforadvancingboneregeneration AT junseoklee developmentofmdm2targetingprotacforadvancingboneregeneration AT soonchullee developmentofmdm2targetingprotacforadvancingboneregeneration AT junwonchoi developmentofmdm2targetingprotacforadvancingboneregeneration AT jinmankim developmentofmdm2targetingprotacforadvancingboneregeneration |