Identification of C/EBPδ-Modifying Compounds as Potential Anticancer Agents Using a High-Throughput Drug Screen

Area of Science:

• Molecular Biology
• Cancer Research
• Pharmacology

Background:

• CCAAT/enhancer-binding protein delta (C/EBPδ) has dual roles in cancer, promoting progression in some cancers but limiting it in pancreatic ductal adenocarcinoma (PDAC).
• Targeting C/EBPδ offers clinical potential, but few compounds are known to modulate its activity.

Purpose of the Study:

• To identify novel small molecules that modulate C/EBPδ transcriptional activity.
• To understand the regulatory mechanisms of C/EBPδ in pancreatic ductal adenocarcinoma (PDAC).

Main Methods:

• High-throughput compound screening using a novel eGFP reporter system.
• Pathway enrichment analysis to identify targeted pathways.
• Validation of identified compounds in PDAC cell models.

Main Results:

• Identified 22 potent inducers and 18 inhibitors of C/EBPδ activity from 1402 small molecule inhibitors.
• Cell cycle inhibition generally increased C/EBPδ activity, while PI3K/Akt/mTOR inhibitors decreased it.
• Four multi-cyclin-dependent kinase (CDK) inhibitors, potent C/EBPδ activators, limited PDAC cell clonal expansion.

Conclusions:

• This study provides a valuable set of C/EBPδ-modulating compounds for preclinical research.
• Findings enhance understanding of C/EBPδ regulation, particularly in PDAC.
• Cell cycle regulation is a key mechanism influencing C/EBPδ activity in PDAC.