Discovery of a Potent and Selective ATAD2 Bromodomain Inhibitor with Antiproliferative Activity in Breast Cancer...

Area of Science:

• Epigenetics and Cancer Therapeutics
• Small Molecule Drug Discovery

Background:

• The bromodomain-containing protein ATAD2 is overexpressed in numerous cancers, presenting a potential oncology target.
• Existing small molecule inhibitors of ATAD2 have shown limited cellular efficacy, necessitating the development of improved agents.

Purpose of the Study:

• To identify novel, potent, and selective inhibitors of ATAD2.
• To optimize initial hits for improved cellular activity and drug-like properties.
• To evaluate the efficacy of optimized inhibitors in relevant cancer models.

Main Methods:

• High-throughput screening (HTS) was employed to identify initial ATAD2 inhibitor hits.
• The bromodomain region was confirmed as the primary site of inhibition.
• Medicinal chemistry optimization focused on enhancing potency, selectivity, and cell permeability.

Main Results:

• A novel series of ATAD2 inhibitors was identified through HTS.
• Compound 5 (AZ13824374) emerged as a highly potent and selective ATAD2 inhibitor.
• Compound 5 demonstrated cellular target engagement and antiproliferative effects in breast cancer models.

Conclusions:

• Compound 5 (AZ13824374) represents a promising lead compound for further development as an oncology therapeutic.
• Targeting ATAD2 via potent and selective inhibition shows potential for treating ATAD2-overexpressing cancers, including breast cancer.