机构：[1]Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.四川大学华西医院[2]Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.四川大学华西医院[3]Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.四川大学华西医院[4]Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.[5]Department of Nanomedicine & Drug Targeting, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands.[6]Medical Research Center, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu 610031, China.
The immune checkpoint blockade represents a pivotal strategy for tumor immunotherapy. At present, various programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) monoclonal antibodies have been successfully applied to tumor treatment. Additionally, numerous small molecule inhibitors of the PD-1/PD-L1 interaction have also been developed, with some advancing into clinical trials. Here, a novel PD-L1 proteolysis-targeting chimera (PROTAC) library was designed and synthesized utilizing the PD-L1 inhibitor BMS202 and the E3 ligand PG as foundational components. Among these, we identified a highly potent molecule PA8 for PD-L1 degradation in 4T1 cells (DC50 = 0.609 μM). Significantly, compound PA8 potentially inhibits 4T1 cell growth both in vitro and in vivo. Further mechanistic studies revealed that PA8 effectively promoted the immune activation of model mice. Thus, these results suggest that PA8 could be a novel strategy for cancer immunotherapy in the 4T1 tumor model. Although PA8 exhibits weaker degradation activity in some human cancer cells, it still provides a certain basis for further research on PD-L1 PROTAC.
基金：
This work was supported by the National Natural Science
Foundation of China (82303606), the Institutional Research
Fund from Sichuan University (2022SCUH0047) and the
Sichuan Science and Technology Program (2023YFH0097 and
2023NSFSC1844), the Da zhou Sichuan University project of
Da zhou Bureau Science and Technology (No. 2021CDDZ-
26), and The Third People’s Hospital of Chengdu Scientific
Research Project (2023PI25). The Analytical & Testing
Center of Sichuan University is gratefully acknowledged for
the characterization of the new compounds.
第一作者机构：[1]Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.[2]Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.[3]Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Zhang Hongjia,Zhang Yan,Feng Zhanzhan,et al.Discovery of Novel Proteolysis-Targeting Chimera Molecules as Degraders of Programmed Cell Death-Ligand 1 for Breast Cancer Therapy[J].Journal Of Medicinal Chemistry.2024,doi:10.1021/acs.jmedchem.3c02259.
APA：
Zhang Hongjia,Zhang Yan,Feng Zhanzhan,Shuai Ming,Ma Xinyu...&Li Rui.(2024).Discovery of Novel Proteolysis-Targeting Chimera Molecules as Degraders of Programmed Cell Death-Ligand 1 for Breast Cancer Therapy.Journal Of Medicinal Chemistry,,
MLA：
Zhang Hongjia,et al."Discovery of Novel Proteolysis-Targeting Chimera Molecules as Degraders of Programmed Cell Death-Ligand 1 for Breast Cancer Therapy".Journal Of Medicinal Chemistry .(2024)
医学