蛋白水解靶向嵌合体 (PROTAC) 通过靶蛋白降解改变了药物开发的范式。然而，由于不加选择的降解以及抑制剂作为蛋白质靶向弹头的用途，PROTAC 可能对正常细胞表现出全身毒性。在这里，我们提出了一种开发可激活 PROTAC 的新策略，用于组蛋白脱乙酰酶 (HDAC) 的细胞特异性降解，通过弹头的笼罩将副作用降至最低。分子对接表明 HDAC 抑制剂的羟基对于靶向至关重要。通过用 NAD(P)H 的底物：在癌细胞中过度表达的醌氧化还原酶 1 (NQO1) 封闭羟基，设计了一种酶激活的 PROTAC。我们证明笼状 PROTAC 可以响应 NQO1 转化为其活性形式。可酶激活的 PROTAC 可以有效且特异性地降解 HDAC6，并在 NQO1 阳性细胞中发挥抗增殖活性。通过设计 H2O2 响应性 PROTAC，在 H2O2 升高的细胞中特异性降解 HDAC6，进一步证明了该设计的通用性。笼罩靶蛋白配体的策略将为开发具有高特异性和最小副作用的可激活PROTAC提供新的维度。

Proteolysis targeting chimeras (PROTACs) have shifted the paradigm for drug development via target protein degradation. However, PROTACs may exhibit systemic toxicity to normal cells due to indiscriminate degradation and the utility of inhibitors as a warhead for protein targeting. Here, we propose a new strategy for developing activatable PROTACs for cell-specific degradation of histone deacetylase (HDAC) with minimal side effects via caging of the warhead. Molecular docking reveals that the hydroxyl group of the HDAC inhibitor is crucial for targeting. An enzyme-activatable PROTAC is designed by caging the hydroxyl group with the substrate for NAD(P)H: quinone oxidoreductase 1 (NQO1) overexpressed in cancer cells. We demonstrate that the caged PROTAC can be converted to its active form in response to NQO1. The enzyme-activatable PROTAC allows the efficient and specific degradation of HDAC6 and exerts antiproliferative activity in NQO1-positive cells. The generalizability of the design is further demonstrated by engineering a H2O2-responsive PROTAC for specific degradation of HDAC6 in cells with elevated H2O2. The strategy of caging the ligand for target proteins would afford a new dimension for developing activatable PROTACs with high specificity and minimal side effects.