Discovery and Pharmacological Evaluation of Potent and Highly Selective PARP1 Inhibitors

The first-generation approved PARP inhibitors (PARPi) inhibit both PARP1 and PARP2, which may result in significant hematological toxicity. To overcome this potential issue, we designed and synthesized a series of small molecules that are highly selective PARP1 inhibitors. Among these, (<i>S</i>)-<b>G9</b> exhibited an IC₅₀ of 0.19 nM against PARP1, with a remarkable 137-fold selectivity over PARP2 and high antiproliferative activity in BRCA mutant MDA-MB-436 cells with an IC₅₀ of 1.5 nM. Furthermore, (<i>S</i>)-<b>G9</b> is a PARP1 selective trapper, with a thousand-fold less activity toward PARP2. (<i>S</i>)-<b>G9</b> inhibited tumor growth in the BRCA mutant MDA-MB-436 xenograft model and showed synergistic efficacy in combination with irinotecan in the HCT116 xenograft model, suggesting that it could be a promising candidate drug combined with chemotherapy for the treatment of cancer. These findings indicate that the strategy proposed in this study is highly significant for the development of selective PARP1 inhibitors.