The camptothecin derivatives topoisomerase I (TOP1) inhibitors, irinotecan and topotecan, are FDA approved for the treatment of colorectal, ovarian, lung and breast cancers. Because of the chemical instability of camptothecins, short plasma half-life, drug efflux by the multidrug-resistance ABC transporters, and the severe diarrhea produced by irinotecan, indenoisoquinoline TOP1 inhibitors (LMP400, LMP776, and LMP744), which overcome these limitations, have been developed and are in clinical development. Further modifications of the indenoisoquinolines led to the fluoroindenoisoquinolines, one of which, LMP517, is the focus of this study. LMP517 showed better antitumor activity than its parent compound LMP744 against H82 (small cell lung cancer) xenografts. Genetic analyses in DT40 cells showed a dual TOP1 and TOP2 signature with selectivity of LMP517 for DNA repair-deficient tyrosyl DNA phosphodiesterase 2 (TDP2)- and Ku70-knockout cells. RADAR assays revealed that LMP517, and to a lesser extent LMP744, induce TOP2 cleavage complexes (TOP2cc) in addition to TOP1ccs. Histone γH2AX detection showed that, unlike classical TOP1 inhibitors, LMP517 targets cells independently of their position in the cell cycle. Our study establishes LMP517 as a dual TOP1 and TOP2 inhibitor with therapeutic potential.

中文翻译：

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茚并异喹啉 LMP517：一种针对 TOP1 和 TOP2 的新型抗肿瘤剂

喜树碱衍生物拓扑异构酶 I (TOP1) 抑制剂伊立替康和拓扑替康被 FDA 批准用于治疗结直肠癌、卵巢癌、肺癌和乳腺癌。由于喜树碱的化学不稳定性、血浆半衰期短、多药耐药性 ABC 转运蛋白的药物外排以及伊立替康、茚并异喹啉 TOP1 抑制剂（LMP400、LMP776 和 LMP744）产生的严重腹泻，克服了这些限制，已开发并处于临床开发阶段。对茚并异喹啉的进一步修饰产生了氟茚并异喹啉，其中之一，LMP517，是本研究的重点。LMP517 对 H82（小细胞肺癌）异种移植物显示出比其母体化合物 LMP744 更好的抗肿瘤活性。DT40 细胞中的遗传分析显示双重 TOP1 和 TOP2 特征以及 LMP517 对 DNA 修复缺陷型酪氨酰 DNA 磷酸二酯酶 2 (TDP2) 和 Ku70 敲除细胞的选择性。RADAR 分析显示，除了 TOP1ccs 外，LMP517 和在较小程度上的 LMP744 还诱导 TOP2 切割复合物 (TOP2cc)。组蛋白 γH2AX 检测表明，与经典的 TOP1 抑制剂不同，LMP517 的靶向细胞与细胞周期中的位置无关。我们的研究将 LMP517 确立为具有治疗潜力的双重 TOP1 和 TOP2 抑制剂。LMP517 靶向细胞，与其在细胞周期中的位置无关。我们的研究将 LMP517 确立为具有治疗潜力的双重 TOP1 和 TOP2 抑制剂。LMP517 靶向细胞，与其在细胞周期中的位置无关。我们的研究将 LMP517 确立为具有治疗潜力的双重 TOP1 和 TOP2 抑制剂。