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Small molecule targeting FOXM1 DNA binding domain exhibits anti-tumor activity in ovarian cancer
Zaixin Zhang1, Si-Tu Xue2, Yan Gao2
1Key Laboratory of Experimental Teratology, Ministry of Education, Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Abstract:
FOXM1 is a potent oncogenic transcription factor essential for cancer initiation, progression, and drug resistance. FOXM1 regulatory network is a major predictor of adverse outcomes in various human cancers. Inhibition of FOXM1 transcription factor function is a potential strategy in cancer treatment. In this study, we performed structure-based in silico screening to discover small molecules targeting the FOXM1 DNA-binding domain (DBD). Compound XST-20 was identified to effectively suppress FOXM1 transcriptional activities and inhibit ovarian cancer cell proliferation. XST-20 directly interacts with the FOXM1 DNA-binding domain determined by SPR assay. Furthermore, XST-20 was found to significantly reduce the colony-forming efficiency and induce cell cycle arrest and apoptosis. Our study provides a lead compound of FOXM1 inhibitor which may serve as a potential targeted therapy agent for ovarian cancer.
Insights
Scientists discovered a new compound, XST-20, that inhibits the FOXM1 transcription factor. This FOXM1 inhibitor shows promise for treating ovarian cancer by reducing cell proliferation and inducing cell death.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The FOXM1 transcription factor is crucial for cancer development and resistance to therapies.
- Targeting FOXM1 presents a potential strategy for cancer treatment.
Purpose of the Study:
- To identify small molecules that inhibit the FOXM1 transcription factor's DNA-binding domain (DBD).
- To evaluate the efficacy of identified compounds in ovarian cancer models.
Main Methods:
- Structure-based in silico screening was employed to find FOXM1 DBD inhibitors.
- Compound XST-20 was selected for further in vitro and in vivo validation.
- Surface Plasmon Resonance (SPR) assay confirmed direct interaction between XST-20 and FOXM1 DBD.
Main Results:
- Compound XST-20 effectively suppressed FOXM1 transcriptional activity.
- XST-20 significantly inhibited ovarian cancer cell proliferation and colony formation.
- XST-20 induced cell cycle arrest and apoptosis in ovarian cancer cells.
Conclusions:
- XST-20 is a potent FOXM1 inhibitor that directly targets the FOXM1 DNA-binding domain.
- XST-20 demonstrates therapeutic potential as a targeted therapy agent for ovarian cancer.
