Mammalian cells replicate ~ 3 × 10⁹ base pairs per cell cycle. One of the key molecules that slows down the cell cycle and prevents excessive DNA damage upon DNA replication stress is the checkpoint kinase ataxia-telangiectasia-and-RAD3-related (ATR). Proteolysis-targeting-chimeras (PROTACs) are an innovative pharmacological invention to molecularly dissect, biologically understand, and therapeutically assess catalytic and non-catalytic functions of enzymes. This work defines the first-in-class ATR PROTAC, Abd110/Ramotac-1. It is derived from the ATR inhibitor VE-821 and recruits the E3 ubiquitin-ligase component cereblon to ATR. Abd110 eliminates ATR rapidly in human leukemic cells. This mechanism provokes DNA replication catastrophe and augments anti-leukemic effects of the clinically used ribonucleotide reductase-2 inhibitor hydroxyurea. Moreover, Abd110 is more effective than VE-821 against human primary leukemic cells but spares normal primary immune cells. CRISPR-Cas9 screens show that ATR is a dependency factor in 116 myeloid and lymphoid leukemia cells. Treatment of wild-type but not of cereblon knockout cells with Abd110 stalls their proliferation which verifies that ATR elimination is the primary mechanism of Abd110. Altogether, our findings demonstrate specific anti-leukemic effects of an ATR PROTAC.

中文翻译：

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ATR 的药理降解可诱导白血病细胞抗增殖 DNA 复制应激

哺乳动物细胞每个细胞周期复制约 3 × 10 ⁹个碱基对。检查点激酶共济失调毛细血管扩张和 RAD3 相关 (ATR) 是减缓细胞周期并防止 DNA 复制应激时过度 DNA 损伤的关键分子之一。蛋白水解靶向嵌合体 (PROTAC) 是一项创新的药理学发明，可对酶的催化和非催化功能进行分子剖析、生物学理解和治疗评估。这项工作定义了一流的 ATR PROTAC，Abd110/Ramotac-1。它源自 ATR 抑制剂 VE-821，并将 E3 泛素连接酶成分 cereblon 募集至 ATR。 Abd110 可快速消除人类白血病细胞中的 ATR。这种机制会引发 DNA 复制灾难，并增强临床使用的核糖核苷酸还原酶 2 抑制剂羟基脲的抗白血病作用。此外，Abd110 对人类原代白血病细胞比 VE-821 更有效，但不会影响正常的原代免疫细胞。 CRISPR-Cas9 筛选显示 ATR 是 116 个骨髓和淋巴白血病细胞的依赖性因子。用 Abd110 处理野生型细胞（而非小脑敲除细胞）可阻止其增殖，这证实了 ATR 消除是 Abd110 的主要机制。总而言之，我们的研究结果证明了 ATR PROTAC 的特定抗白血病作用。