Identification of Potential RBPJ-Specific Inhibitors for Blocking Notch Signaling in Breast Cancer Using a Drug...

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Notch signaling is crucial for tissue homeostasis but aberrant activation drives breast cancer.
• Existing Notch inhibitors have significant side effects, leading to discontinued clinical trials.
• Targeting RBPJ, a key transcriptional activator in the Notch pathway, presents a promising strategy for safer inhibition.

Purpose of the Study:

• To identify novel, specific inhibitors of RBPJ using a drug repurposing approach.
• To evaluate the efficacy of identified compounds in blocking RBPJ-dependent transcription and inhibiting breast cancer growth.
• To validate fidaxomicin as a potential therapeutic agent for breast cancer treatment.

Main Methods:

• Utilized a drug repurposing strategy combined with molecular docking and dynamic simulations on a database of over 10,527 compounds.
• Screened and selected top-performing compounds for in vitro cellular assays.
• Conducted in vivo anticancer investigations to assess therapeutic potential.

Main Results:

• Identified fidaxomicin, an FDA-approved antibiotic, as a potent RBPJ inhibitor.
• Experimentally verified fidaxomicin's ability to block RBPJ-dependent transcription.
• Demonstrated significant suppression of breast cancer growth by fidaxomicin in both in vitro and in vivo models.

Conclusions:

• Fidaxomicin effectively suppresses Notch signaling by inhibiting RBPJ.
• Fidaxomicin shows potential for repurposing as a novel and safer treatment for breast cancer.
• This discovery opens new avenues for breast cancer therapy targeting the Notch pathway.