Chen Yanchi, Zhang Lina, Fang Lincheng, Chen Chengjie, Zhang Dong, Peng Tao
State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.
National Key Laboratory of Non-Food Biomass Energy Technology, National Engineering Research Center for Non-Food Biorefinery, Institute of Grand Health, Guangxi Academy of Sciences, 98 Daling Road, Nanning 530007, China.
JACS Au. 2024 May 16;4(7):2564-2577. doi: 10.1021/jacsau.4c00298. eCollection 2024 Jul 22.
As an emerging therapeutic modality, proteolysis targeting chimeras (PROTACs) indiscriminately degrade proteins in both healthy and diseased cells, posing a risk of on-target off-site toxicity in normal tissues. Herein, we present the modular development of enzyme-activatable PROTACs, which utilize enzyme-recognition moieties to block protein degradation activities and can be specifically activated by elevated enzymes in cancer cells to enable cell-selective protein degradation and cancer targeting. We identified the methylene alkoxy carbamate (MAC) unit as an optimal self-immolative linker, possessing high stability and release efficiency for conjugating enzyme-recognition moieties with PROTACs. Leveraging the MAC linker, we developed a series of enzyme-activatable PROTACs, harnessing distinct enzymes for cancer-cell-selective protein degradation. Significantly, we introduced the first dual-enzyme-activatable PROTAC that requires the presence of two cancer-associated enzymes for activation, demonstrating highly selective protein degradation in cancer cells over nonmalignant cells, potent antitumor efficacy, and no off-tumor toxicity to normal tissues. The broad applicability of enzyme-activatable PROTACs was further demonstrated by caging other PROTACs via the MAC linker to target different proteins and E3 ligases. Our work underscores the substantial potential of enzyme-activatable PROTACs in overcoming the off-site toxicity associated with conventional PROTACs and offers new opportunities for targeted cancer treatment.
作为一种新兴的治疗方式，靶向蛋白降解嵌合体（PROTACs）会不加区分地降解健康细胞和病变细胞中的蛋白质，在正常组织中存在脱靶毒性的风险。在此，我们展示了酶激活型PROTACs的模块化开发，其利用酶识别部分来阻断蛋白质降解活性，并可被癌细胞中升高的酶特异性激活，以实现细胞选择性蛋白质降解和癌症靶向。我们确定亚甲基烷氧基氨基甲酸酯（MAC）单元为最佳的自裂解连接子，在将酶识别部分与PROTACs偶联时具有高稳定性和释放效率。利用MAC连接子，我们开发了一系列酶激活型PROTACs，利用不同的酶实现癌细胞选择性蛋白质降解。值得注意的是，我们引入了首个双酶激活型PROTAC，其需要两种癌症相关酶的存在才能激活，证明在癌细胞中比非恶性细胞具有高度选择性的蛋白质降解、强大的抗肿瘤功效，且对正常组织无肿瘤外毒性。通过使用MAC连接子封闭其他PROTACs以靶向不同蛋白质和E3连接酶，进一步证明了酶激活型PROTACs的广泛适用性。我们的工作强调了酶激活型PROTACs在克服与传统PROTACs相关的脱靶毒性方面的巨大潜力，并为靶向癌症治疗提供了新机会。
