A novel PARP-ATR dual inhibitor exhibits anti-triple-negative breast cancer activity by inducing excessive DNA damage in the mitotic phase.

Triple-negative breast cancer (TNBC), a particularly aggressive breast carcinoma subtype, exhibits poor clinical outcomes and elevated mortality rates. The therapeutic response to PARP inhibitors (PARPi) is significantly improved in TNBC patients harboring breast cancer susceptibility gene 1/2 (BRCA1/2) mutations compared to naïve patients. Preclinical studies suggested that combination therapy using PARPi and ATR inhibitor (ATRi), which synergistically blocks DNA repair and compromises cell cycle progression, showed promising activity in different cancer models, including TNBC. Unfortunately, the clinical development of this therapy strategy was limited by the dose-limited tolerability of the combination. Here, we reported the discovery of a first-in-class novel PARP-ATR dual inhibitor through rational drug design and medicinal chemistry optimization. Bioactivity evaluations identified an active lead known as PAB-13, which induced synthetic lethality through simultaneous inhibition of PARP and ATR in various TNBC cell lines. Compared with PARPi and ATRi combined treatment, PAB-13 promoted cell cycle progression into the mitotic phase in the context of DNA damage. PAB-13 also demonstrated superior anti-tumor activity compared to PARPi or ATRi alone in the TNBC xenograft mouse model. Our discovery provides proof-of-concept for the bifunctional targeting of PARP and ATR pathways through a single molecule, which opens a new opportunity in developing an innovative treatment method for TNBC.