Combining Data-Driven and Structure-Based Approaches in Designing Dual PARP1-BRD4 Inhibitors for Breast Cancer...

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Drug Discovery

Background:

• Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors are effective in treating cancers with DNA repair deficiencies through synthetic lethality.
• Simultaneous inhibition of PARP1 and bromodomain-containing protein 4 (BRD4) exhibits synergistic effects on cancer cell death.

Purpose of the Study:

• To develop a novel cheminformatics and structure-based approach for designing dual PARP1-BRD4 inhibitors.
• To identify lead-like molecules with potent anticancer activity.

Main Methods:

• A novel cheminformatics approach combined with structure-based methods was employed.
• Merged pharmacophores were identified, prioritizing phenanthridin-6(5H)-one.
• Rational design and synthesis of small molecules targeting PARP1 and BRD4.

Main Results:

• A designed molecule, HF4, showed low micromolar inhibitory activity against both BRD4 and PARP1.
• HF4 demonstrated potent inhibition of BRD4 BD1 (IC50 = 204 nM).
• HF4 exhibited significant antiproliferative effects in breast cancer cell lines by arresting cell cycle and impeding DNA repair.

Conclusions:

• The developed approach facilitates the design of dual PARP1-BRD4 inhibitors.
• HF4 represents a promising lead compound for breast cancer treatment.
• The methodology can be extended to design inhibitors for other targets.