Jeong Sol, Cha Jae-Kook, Ahmed Wasim, Kim Jaewan, Kim Minsup, Hong Kyung Tae, Choi Wonji, Choi Sunjoo, Yoo Tae Hyeon, An Hyun-Ju, An Seung Chan, Lee Jaemin, Choi Jimin, Kim Sun-Young, Lee Jun-Seok, Lee Soonchul, Choi Junwon, Kim Jin Man
Department of Oral Microbiology and Immunology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, 08826, Republic of Korea.
Department of Periodontology, Research Institute of Periodontal Regeneration, College of Dentistry, Yonsei University, Seoul, 03722, Republic of Korea.
Adv Sci (Weinh). 2025 May;12(19):e2415626. doi: 10.1002/advs.202415626. Epub 2025 Mar 24.
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.
蛋白酶靶向嵌合体（PROTACs）通过泛素-蛋白酶体系统降解靶蛋白。迄今为止，PROTACs主要用于治疗各种疾病；然而，它们尚未应用于再生治疗。在此，这项工作介绍了为骨再生应用定制的靶向MDM2的PROTACs。通过将Nutlin-3和CRBN配体与各种连接子设计相结合，构建了一个MDM2-PROTAC文库。通过多步骤验证过程，这项工作开发出了具有高效降解效率和对生物矿化有强大诱导作用的MDM2-PROTACs（CL144和CL174）。接下来，这项工作进行了全转录组分析以剖析CL144的生物学效应，并揭示了成骨标记基因的上调。此外，CL144分别在局部和全身给药后，在骨移植和卵巢切除（OVX）模型中有效诱导了骨再生。在OVX模型中，CL144与阿仑膦酸钠联合治疗产生了协同效应。总体而言，这项研究证明了MDM2-PROTAC在促进骨再生方面的潜在作用，标志着向扩大PROTAC技术应用迈出的第一步。
