In late mitosis and G1, origins of DNA replication must be “licensed” for use in the upcoming S phase by being encircled by double hexamers of the minichromosome maintenance proteins MCM2–7. A “licensing checkpoint” delays cells in G1until sufficient origins have been licensed, but this checkpoint is lost in cancer cells. Inhibition of licensing can therefore kill cancer cells while only delaying normal cells in G1. In a high-throughput cell-based screen for licensing inhibitors we identified a family of 2-arylquinolin-4-amines, the most potent of which we call RL5a. The binding of the origin recognition complex (ORC) to origin DNA is the first step of the licensing reaction. We show that RL5a prevents ORC forming a tight complex with DNA that is required for MCM2–7 loading. Formation of this ORC-DNA complex requires ATP, and we show that RL5a inhibits ORC allosterically to mimic a lack of ATP.

中文翻译：

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2-Arylquinolin-4-Amines抑制复制许可所需的ORC和DNA之间的高亲和力相互作用。

在有丝分裂晚期和G1期，DNA复制的起点必须被“许可”用于即将出现的S期，方法是被微型染色体维持蛋白MCM2-7的双六聚体所包围。“许可检查点”会延迟G1中的细胞，直到有足够的来源获得许可为止，但是此检查点在癌细胞中丢失了。因此，许可的抑制可以杀死癌细胞，同时仅延迟G1中的正常细胞。在基于通量的高通量细胞筛选许可抑制剂的过程中，我们鉴定了2-芳基喹啉-4-胺家族，我们称其为最强效的RL5a。起源识别复合物（ORC）与起源DNA的结合是许可反应的第一步。我们表明，RL5a可以防止ORC与MCM2-7装载所需的DNA形成紧密的复合物。这种ORC-DNA复合物的形成需要ATP，