连接器
拓扑异构酶
劈理(地质)
核糖核酸
细胞毒性
化学
体外
立体化学
组合化学
生物化学
生物
基因
古生物学
断裂(地质)
计算机科学
操作系统
作者
Wenjie Wang,Sanjoy Kumar Saha,Xi Yang,Yves Pommier,Shar-yin N. Huang
标识
DOI:10.1073/pnas.2218483120
摘要
We designed and carried out a high-throughput screen for compounds that trap topoisomerase III beta (TOP3B poisons) by developing a Comparative Cellular Cytotoxicity Screen. We found a bisacridine compound NSC690634 and a thiacyanine compound NSC96932 that preferentially sensitize cell lines expressing TOP3B, indicating that they target TOP3B. These compounds trap TOP3B cleavage complex (TOP3Bcc) in cells and in vitro and predominately act on RNA, leading to high levels of RNA-TOP3Bccs. NSC690634 also leads to enhanced R-loops in a TOP3B-dependent manner. Preliminary structural activity studies show that the lengths of linkers between the two aromatic moieties in each compound are critical; altering the linker length completely abolishes the trapping of TOP3Bccs. Both of our lead compounds share a similar structural motif, which can serve as a base for further modification. They may also serve in anticancer, antiviral, and/or basic research applications.
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