Design, synthesis and anti-breast cancer activity evaluation of 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-based PARP1/ATR dual inhibitors.

PARP1 inhibitors are FDA-approved for BRCA1/2-mutated breast cancer but show limited efficacy in wild-type cancers and face resistance issues. To overcome these, we designed novel 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-based compounds integrating PARP1 inhibitor pharmacophores with the ATR inhibitor AZD6738 scaffold. Substituent modifications influenced PARP1 and ATR selectivity, yielding dual inhibitors or selective PARP1 inhibitors. Compound 38a, the lead candidate, exhibited potent dual inhibition (IC50 < 20 nM) and strong antitumor effects in MDA-MB-231 (IC50 < 0.048 μM) and MDA-MB-468 (IC50: 0.01 μM) cell lines in vitro. Mechanistically, 38a arrested cell cycle progression, induced apoptosis, inhibited colony formation and migration, and suppressed DNA damage repair pathways, outperforming combined Niraparib and AZD6738. These findings underscore the therapeutic potential of PARP1/ATR dual inhibitors for breast cancer and support further investigation.