PARP1-IN-44 is a derivative of Olaparib and functions as an orally active PARP1 inhibitor with an IC50 of 0.6 nM. It also inhibits PARP2 (IC50 = 1.0 nM) and PARP7 (IC50 = 7.5 nM). PARP1-IN-44 demonstrates selective antiproliferative activity against BRCA-deficient cancer cells with minimal toxicity to normal cells. It induces G2/M phase arrest, promotes apoptosis, increases reactive oxygen species (ROS) levels, and disrupts mitochondrial membrane potential. Additionally, PARP1-IN-44 inhibits PARylation and leads to the accumulation of γH2AX. It activates the cGAS-STING pathway, enhancing the expression of IFN-β and CXCL10. In a CT26 tumor mouse model, PARP1-IN-44 enhances CD8+ T cell infiltration, showcasing significant in vivo antitumor activity.

PARP1:0.6 nM

PARP1-IN-44 (Compound B3) exhibits antiproliferative effects against various tumor cell lines at concentrations of 3.63-100 μM over a period of five days, with IC50 values of 9.70 μM (HCT-15), 5.80 μM (HCC1937), 18.06 μM (HepG2), 16.48 μM (MCF7), 9.88 μM (Capan-1), and 12.48 μM (CT26). It demonstrates excellent safety, showing IC50 values greater than 100 μM for non-cancerous NCM460 and GES-1 cell lines. PARP1-IN-44 at 2.5-10 μM for 48 hours can induce apoptosis and cause cell cycle arrest in HCC1937 cells. Additionally, at the same concentration range for 24 hours, it inhibits PARP1-mediated H2O2-induced DNA damage repair in HCC1937 cells. PARP1-IN-44 also induces ROS accumulation (detected with DCFH-DA probe) and mitochondrial depolarization (evaluated with JC-1 staining) in HCC1937 cells. Furthermore, PARP1-IN-44 at 0.25-2 μM for 72 hours can restore innate immune response in CT26 cells.

PARP1-IN-44, administered orally at doses of 30 and 50 mg/kg once daily for 14 days, demonstrates antitumor activity in BALB/c mice with CT26 tumors.