Substituted Triazole-3,5-Diamine Compounds as Novel Human Topoisomerase III Beta Inhibitors

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Human topoisomerase III beta (hTOP3B) is crucial for genome stability, cellular aging, and viral replication.
• hTOP3B's dual DNA/RNA activity makes it a therapeutic target, particularly for positive-sense ssRNA viruses like Dengue.
• hTOP3B is essential for efficient replication of certain viruses.

Purpose of the Study:

• To identify potential hTOP3B inhibitors using in silico screening of FDA-approved or investigational drugs.
• To evaluate the inhibitory activity of identified compounds against hTOP3B.
• To explore novel therapeutic strategies targeting hTOP3B for antiviral applications.

Main Methods:

• In silico screening of a drug library against hTOP3B.
• Topoisomerase activity assays to measure hTOP3B relaxation activity.
• Synthesis and testing of novel small molecules based on bemcentinib's chemical structure.

Main Results:

• Bemcentinib, an AXL receptor tyrosine kinase inhibitor, was identified as a novel inhibitor of hTOP3B relaxation activity.
• Bemcentinib is the first small molecule demonstrated to inhibit the complete catalytic cycle of hTOP3B.
• Five novel compounds sharing the triazole-diamine moiety of bemcentinib exhibited comparable hTOP3B inhibitory activity (IC50).

Conclusions:

• The study identified bemcentinib and related analogs as potent inhibitors of hTOP3B.
• This research provides a foundation for developing new antiviral agents targeting hTOP3B.
• Exploring tyrosine kinase inhibitors offers a promising strategy for discovering novel topoisomerase inhibitors.