Design and Biological Evaluation of a Potent Dual PARP and BRD4 Inhibitor for Tumor Therapy via Disrupting HRR and BRD4-cJUN-CCL2 Axis

Abstract Inducing homologous recombination repair (HRR) deficiency is an attractive strategy to expand the therapeutic scope of PARP inhibitors. Since BRD4 inhibition impairs HRR function and sensitizes cancer cells to PARP inhibition, we designed and synthesized a series of dual PARP/BRD4 inhibitors. Structure−activity relationship studies identified D6 as a potent dual inhibitor with low nanomolar inhibitory activities against PARP1 and BRD4. D6 exhibited potent antiproliferative activity in MDA-MB-231 and KP4 cells and induced cell cycle arrest, apoptosis, and inhibition of colony formation and metastasis-associated phenotypes. Mechanistically, D6 suppressed the BRD4-cJUN-CCL2 signaling axis, reducing macrophage recruitment and macrophage-mediated cancer cell invasion. In an MDA-MB-231 xenograft model, D6 inhibited tumor growth without obvious toxicity. These findings support D6 as a promising dual PARP/BRD4 inhibitor for cancer therapy.