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, (S)-G9 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, (S)-G9 is a PARP1 selective trapper, with a thousand-fold
less activity toward PARP2. (S)-G9 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.