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Published on: May 5, 2014
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A high-throughput screening identifies MCM chromatin loading inhibitors targeting cells with increased replication
Lucia Falbo1,2, Hervé Técher1, Vincenzo Sannino1
1IFOM-ETS, The AIRC Institute of Molecular Oncology, Milan, Italy.
Iscience
|August 26, 2024
Summary
Researchers identified NSC-95397, a novel inhibitor of DNA replication origin assembly that targets CDC6 protein. This compound effectively induces cell death in rapidly proliferating cancer cells and Xenopus embryos, showing potential as an anti-cancer therapeutic.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- DNA replication initiation is crucial for cell division.
- Origin recognition complex (ORC), CDC6, and CDT1 facilitate MCM helicase loading.
- Targeting replication origin assembly offers a strategy against hyperproliferative cancer cells.
Purpose of the Study:
- To develop a high-throughput screening method to identify inhibitors of MCM helicase loading.
- To discover novel compounds that disrupt replication origin assembly.
- To evaluate the anti-cancer potential of identified inhibitors.
Main Methods:
- High-throughput screening using Xenopus laevis egg extract.
- Identification and characterization of MCM chromatin loading inhibitors.
- Testing drug-induced lethality in human cells and Xenopus embryos.
Main Results:
- NSC-95397 was identified as a potent inhibitor of replication origin assembly.
- NSC-95397 targets the CDC6 protein, promoting its degradation.
- NSC-95397 induced cell death in rapidly proliferating human cells and Xenopus embryos.
Conclusions:
- Disrupting DNA replication origin assembly is an effective strategy for targeting hyperproliferative cells.
- NSC-95397 demonstrates potential as a novel anti-cancer therapeutic agent.
- The identified compound highlights the therapeutic potential of targeting DNA replication machinery.
