Novel Cell Cycle Inhibitors Decrease Primary and Metastatic Breast Cancer Growth In Vivo

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Breast cancer metastasis is a major cause of mortality, necessitating new therapeutic strategies.
• Existing treatments for metastatic breast cancer are limited, highlighting the need for innovative approaches.

Purpose of the Study:

• To identify novel small-molecule compounds for treating metastatic breast cancer.
• To evaluate the efficacy and mechanisms of action of identified compounds.

Main Methods:

• Conducted a small-molecule drug screen using patient-derived circulating tumor cells (CTCs).
• Utilized high-content imaging microscopy to assess compound efficacy in vitro and in vivo.
• Performed bulk RNA sequencing and Gene Ontology analysis to understand molecular mechanisms.

Main Results:

• Identified five meriolin derivatives with cyclin-dependent kinase (CDK-2/9) inhibitory activity.
• Validated compound efficacy in inhibiting cell cycle, tumor growth, and metastasis in mouse models.
• Transcriptome profiling revealed cell cycle regulation pathway alterations.

Conclusions:

• The identified meriolin derivatives are promising candidates for breast cancer treatment.
• Integrated drug screening, transcriptomics, and in vivo validation offer a robust approach for drug discovery.