Hongjia Zhang, Yan Zhang, Zhanzhan Feng, Ming Shuai, Xinyu Ma, Shirui Wang, Su Yu, Rui Deng, Dan Luo, Jianyou Shi*, Chunlan Pu* and Rui Li*,
{"title":"发现新型蛋白质分解靶向嵌合体分子作为程序性细胞死亡配体 1 的降解剂,用于乳腺癌治疗。","authors":"Hongjia Zhang, Yan Zhang, Zhanzhan Feng, Ming Shuai, Xinyu Ma, Shirui Wang, Su Yu, Rui Deng, Dan Luo, Jianyou Shi*, Chunlan Pu* and Rui Li*, ","doi":"10.1021/acs.jmedchem.3c02259","DOIUrl":null,"url":null,"abstract":"<p >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 <b>BMS202</b> and the E3 ligand <b>PG</b> as foundational components. Among these, we identified a highly potent molecule <b>PA8</b> for PD-L1 degradation in 4T1 cells (DC<sub>50</sub> = 0.609 μM). Significantly, compound <b>PA8</b> potentially inhibits 4T1 cell growth both <i>in vitro</i> and <i>in vivo</i>. Further mechanistic studies revealed that <b>PA8</b> effectively promoted the immune activation of model mice. Thus, these results suggest that <b>PA8</b> could be a novel strategy for cancer immunotherapy in the 4T1 tumor model. Although <b>PA8</b> exhibits weaker degradation activity in some human cancer cells, it still provides a certain basis for further research on PD-L1 PROTAC.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of Novel Proteolysis-Targeting Chimera Molecules as Degraders of Programmed Cell Death-Ligand 1 for Breast Cancer Therapy\",\"authors\":\"Hongjia Zhang, Yan Zhang, Zhanzhan Feng, Ming Shuai, Xinyu Ma, Shirui Wang, Su Yu, Rui Deng, Dan Luo, Jianyou Shi*, Chunlan Pu* and Rui Li*, \",\"doi\":\"10.1021/acs.jmedchem.3c02259\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >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 <b>BMS202</b> and the E3 ligand <b>PG</b> as foundational components. Among these, we identified a highly potent molecule <b>PA8</b> for PD-L1 degradation in 4T1 cells (DC<sub>50</sub> = 0.609 μM). Significantly, compound <b>PA8</b> potentially inhibits 4T1 cell growth both <i>in vitro</i> and <i>in vivo</i>. Further mechanistic studies revealed that <b>PA8</b> effectively promoted the immune activation of model mice. Thus, these results suggest that <b>PA8</b> could be a novel strategy for cancer immunotherapy in the 4T1 tumor model. Although <b>PA8</b> exhibits weaker degradation activity in some human cancer cells, it still provides a certain basis for further research on PD-L1 PROTAC.</p>\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2024-06-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c02259\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c02259","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Discovery of Novel Proteolysis-Targeting Chimera Molecules as Degraders of Programmed Cell Death-Ligand 1 for Breast Cancer Therapy
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.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.