Discovery of 4‑Hydroxyquinazoline Derivatives as Small Molecular BET/PARP1 Inhibitors That Induce Defective Homologous Recombination and Lead to Synthetic Lethality for Triple-Negative Breast Cancer Therapy

The effective potency and resistance
of poly­(ADP-ribose) polymerase
(PARP) inhibitors limit their application. Here, we exploit a new
paradigm that mimics the effects of breast cancer susceptibility genes
(BRCA) mutations to trigger the possibility of synthetic lethality,
based on the previous discovery of a potential synthetic lethality
effect between bromodomain-containing protein 4 (BRD4) and PARP1.
Consequently, the present study describes compound BP44 with high selectivity for BRD4 and PARP1. Fortunately, BP44 inhibits the homologous recombination in triple-negative breast
cancer (TNBC) and triggers synthetic lethality, thus leading to cell
cycle arrest and DNA damage. In conclusion, we optimized the BRD4-PARP1
inhibitor based on previous studies, and we expect it to become a
candidate drug for the treatment of TNBC in the future. This strategy
aims to expand the use of PARPi in BRCA-competent TNBC, making an
innovative approach to address unmet oncology needs.