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

Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors have revolutionized the treatment of many cancers with DNA-repairing deficiencies via synthetic lethality. Advocated by the polypharmacology concept, recent evidence discovered that a significantly synergistic effect in increasing the death of cancer cells was observed by simultaneously perturbating the enzymatic activities of bromodomain-containing protein 4 (BRD4) and PARP1. Here, we developed a novel cheminformatics approach combined with a structure-based method aiming to facilitate the design of dual PARP1-BRD4 inhibitors. Instead of linking pharmacophores, the developed approach first identified merged pharmacophores (a pool of amide-containing ring systems), from which phenanthridin-6(5