Laboratory of Molecular Pharmacology, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2218483120. doi: 10.1073/pnas.2218483120. Epub 2023 Aug 14.
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.
我们设计并开展了一个高通量筛选化合物的实验，通过开发一种比较细胞细胞毒性筛选方法，来筛选能够捕获拓扑异构酶 IIIβ（TOP3B 抑制剂）的化合物。我们发现了一个双吖啶化合物 NSC690634 和一个硫代花菁化合物 NSC96932，它们能够优先敏感表达 TOP3B 的细胞系，表明它们是靶向 TOP3B 的。这些化合物能够在细胞内和体外捕获 TOP3B 切割复合物（TOP3Bcc），并主要作用于 RNA，导致高水平的 RNA-TOP3Bccs。NSC690634 还能够以 TOP3B 依赖的方式增强 R 环。初步的结构活性研究表明，每个化合物中两个芳基部分之间的连接体的长度是至关重要的；改变连接体的长度完全消除了 TOP3Bcc 的捕获。我们的两个先导化合物都具有相似的结构基序，这可以作为进一步修饰的基础。它们也可能用于抗癌、抗病毒和/或基础研究应用。
