PARP1-IN-40 is a highly selective and orally active PARP1 inhibitor with an IC50 of 0.19 nM for PARP1 and 26 nM for PARP2. By inhibiting PARP1, it induces DNA damage accumulation, effectively killing tumor cells. It demonstrates significant antitumor activity against BRCA-mutated MDA-MB-436 cells. Additionally, PARP1-IN-40 can be used in combination with chemotherapy for related cancer research.

PARP1-IN-40 (Compound (S)-G9) effectively arrests the MDA-MB-436 cell cycle at the G2/M phase and inhibits proliferation at concentrations of 1-100 nM over 3 days. At concentrations of 0.1-1000 nM for 3 days, it induces DNA damage and double-strand breaks in MDA-MB-436 cells. In A549 PARP1 gene knockout cells, PARP1-IN-40 shows minimal activity (IC50 > 9.8 μM) when applied at concentrations of 0.1-10000 nM for 1 hour, indicating its action is entirely PARP1-dependent and exhibits weak PARP2 inhibition, thereby reducing traditional PARPi toxicity risks. It efficiently captures PARP1-DNA complexes at 0.1-10000 nM within 1 hour (EC50 = 1.9 nM), requiring a significantly higher concentration to capture PARP2, acting as a PARP1-selective trapping agent. Finally, at concentrations of 0.1-20000 nM over 10 days, it selectively kills BRCA mutant cells, confirming its synthetic lethality mechanism which depends on homologous recombination deficiency.

PARP1-IN-40 (Compound (S)-G9) administered orally at doses of 0.3-3 mg/kg for 27 consecutive days effectively inhibits the growth of BRCA-mutated tumors in the MDA-MB-231 xenograft mouse model, exhibiting no significant toxicity. In the HCT116 xenograft mouse model, PARP1-IN-40 at 1-3 mg/kg orally for 14 consecutive days enhances the efficacy of chemotherapy. Additionally, this compound demonstrates high safety in BALB/C nude mice when given once at 30-300 mg/kg orally, or repeatedly at 30-100 mg/kg for 14 days.