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Updated: Jul 19, 2025

Simple and Fast Rolling Circle Amplification-Based Detection of Topoisomerase 1 Activity in Crude Biological Samples
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Identification and characterization of topoisomerase III beta poisons

Wenjie Wang1, Sourav Saha1, Xi Yang1

  • 1Laboratory of Molecular Pharmacology, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.

Proceedings of the National Academy of Sciences of the United States of America
|August 14, 2023
PubMed

Insights

Researchers identified novel compounds, NSC690634 and NSC96932, that specifically target and trap topoisomerase III beta (TOP3B) by forming RNA-TOP3B complexes, with potential applications in cancer and antiviral therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Topoisomerase III beta (TOP3B) is crucial for DNA and RNA metabolism.
  • Developing targeted inhibitors for TOP3B is a promising therapeutic strategy.

Purpose of the Study:

  • To identify and characterize compounds that selectively trap TOP3B (TOP3B poisons).
  • To explore the mechanism of action and structural requirements of these TOP3B poisons.

Main Methods:

  • High-throughput screening using a Comparative Cellular Cytotoxicity Screen.
  • In vitro and cellular assays to detect TOP3B cleavage complex (TOP3Bcc) trapping.
  • Preliminary structural activity relationship (SAR) studies.

Main Results:

  • Identified bisacridine NSC690634 and thiacyanine NSC96932 as TOP3B-targeting compounds.
  • These compounds trap TOP3Bcc, predominantly acting on RNA to form RNA-TOP3Bccs.
  • Linker length in the compounds is critical for TOP3Bcc trapping; NSC690634 enhances R-loops in a TOP3B-dependent manner.

Conclusions:

  • NSC690634 and NSC96932 are effective TOP3B poisons with a shared structural motif.
  • These compounds demonstrate potential for anticancer and antiviral applications.
  • Further structural modifications could optimize their therapeutic efficacy.
Keywords:
TOP3Banti-cancerinhibitor screen

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