Discovery of novel ATAD2 bromodomain inhibitors that trigger apoptosis and autophagy in breast cells by...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The ATAD2 protein is implicated in various cancers and represents a potential therapeutic target.
• Understanding ATAD2's role is crucial for developing novel cancer treatments.

Purpose of the Study:

• To discover potent ATAD2 inhibitors.
• To elucidate the mechanisms of ATAD2 inhibition in breast cancer.

Main Methods:

• Structure-based virtual screening.
• Biochemical analyses.
• Cell proliferation assays and Western blotting.

Main Results:

• A novel ATAD2 bromodomain inhibitor, AM879, was identified with potent inhibitory activity (IC50 = 3565 nM) and selectivity over BRD2-4.
• AM879 inhibited MDA-MB-231 breast cancer cell proliferation (IC50 = 2.43 µM), suppressed c-Myc expression, and induced apoptosis.
• AM879 also induced autophagy via the PI3K-AKT-mTOR signaling pathway.

Conclusions:

• Development of potent ATAD2 inhibitors with novel scaffolds for breast cancer therapy.
• AM879 demonstrates potential as a therapeutic agent for breast cancer by targeting ATAD2.
• Further investigation into ATAD2 inhibitors could lead to new treatment strategies.