BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen

Area of Science:

• Medicinal Chemistry
• Epigenetics
• Drug Discovery

Background:

• Bromodomain and Extra-Terminal domain (BET) proteins (BrdT, Brd4) are key epigenetic regulators.
• Inhibition of BET proteins presents therapeutic potential in contraception, cancer, and heart disease.

Purpose of the Study:

• To discover and develop novel, easily synthesized dihydropyridopyrimidine-based inhibitors targeting BET proteins.
• To characterize the potency, selectivity, and binding modes of these novel inhibitors.

Main Methods:

• Virtual screening to identify initial inhibitor scaffolds.
• Synthesis of dihydropyridopyrimidine derivatives.
• Fluorescence anisotropy assays for binding affinity determination.
• Co-crystallization with Brd4 to elucidate ligand-protein interactions.
• Structure-activity relationship (SAR) studies.

Main Results:

• Identified a dihydropyridopyrimidine scaffold as a potent and selective pan-BET inhibitor.
• Demonstrated the importance of uracil moiety substitution for optimizing potency and selectivity.
• Determined the ligand binding pose of a key inhibitor (Compound 3) with Brd4 via co-crystallization.
• Developed additional derivatives with submicromolar affinity and demonstrated cellular target engagement.

Conclusions:

• Novel, easily synthesized dihydropyridopyrimidines are effective BET inhibitors.
• These compounds represent promising candidates for further development in epigenetic therapies.
• The findings contribute valuable structure-activity relationship insights to the field of bromodomain inhibitor development.