Identification of 3-arylquinoxalin-2(1H)-one derivatives targeting BRD4 BD1 as efficient anticancer agents

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Cancer Research

Background:

• Bromodomain 4 (BRD4) is a crucial epigenetic reader protein implicated in various cancers.
• Developing selective BRD4 inhibitors, particularly for the BD1 domain, is vital for overcoming limitations of existing therapies.

Purpose of the Study:

• To design and synthesize novel 3-arylquinoxalin-2(1H)-one derivatives as selective BRD4 BD1 inhibitors.
• To evaluate the anti-cancer potential of these compounds, focusing on efficacy, selectivity, and mechanism of action.

Main Methods:

• Scaffold fusion approach for compound design and synthesis.
• In vitro assays to determine BRD4 BD1 inhibitory activity and selectivity.
• Cell-based assays to assess effects on cancer cell migration, proliferation, and apoptosis.
• Mechanistic studies including Western blotting, DNA damage assays, ROS detection, and mitochondrial potential measurement.
• Molecular docking to elucidate binding interactions.

Main Results:

• The optimized compound B12 exhibited potent BRD4 BD1 inhibition (IC50 = 0.82 μM) with 22-fold selectivity over BRD4 BD2.
• B12 effectively suppressed A549 lung cancer cell migration and proliferation (IC50 = 0.73 μM).
• Mechanistic studies revealed B12 induces apoptosis by downregulating c-myc, reducing anti-apoptotic proteins, increasing DNA damage, elevating ROS, and decreasing mitochondrial membrane potential.
• Molecular docking confirmed selective binding of B12 to BRD4 BD1 via key hydrogen bonds.

Conclusions:

• The 3-arylquinoxalin-2(1H)-one scaffold is a promising backbone for developing selective BRD4 inhibitors.
• Compound B12 demonstrates significant anti-cancer activity and favorable properties, warranting further investigation as a potential therapeutic agent.