Discovery of PARP‐1 Inhibitors for Triple‐Negative Breast Cancer via Structure‐Based Virtual High‐Throughput Screening

Abstract Triple‐negative breast cancer (TNBC) is a challenging and complex disease characterized by unique pathogenic features, poor prognosis, and a lack of specific treatment options compared to other breast cancer subtypes. Chemotherapy is currently the primary therapeutic approach, but low response rates highlight the significant need for more efficient therapeutic options. Poly (ADP‐ribose) polymerase 1 (PARP1) plays a critical role in the pathology of various diseases, including TNBC, and inhibiting PARP1 is a promising strategy for treatment, especially in the context of synthetic lethality in BRCA1/2 deficiencies often associated with TNBC. This study utilizes a structure‐based virtual high‐throughput screening of a library of 4.59 million lead‐like compounds from the ZINC database to identify potential inhibitors of PARP‐1 for TNBC treatment. The analysis identified 25 promising hits, further validated for their inhibition activity in vitro. The top 4 ranked compounds were selected based on their inhibition strength. The final hit ZINC000081009201, demonstrated good PARP inhibitory activity with an IC50 value of 1.4767 µM and was identified as having better physicochemical properties and good prospects for subsequent structural optimization to improve its activity to enhance the potency of PARP‐1 inhibitors for TNBC.