SY-589 is a highly potent, selective and orally bioavailable DNA polymerase theta (Polθ) helicase inhibitor with ATPase inhibitory IC50 of 2.29 nM in ADP-Glo assays, inhibits microhomology-mediated end joining (MMEJ) pathway.
SY-589 exhibits cellular antiproliferative activity with IC50 of 2.71 nM against DLD1 BRCA2–/– cells.
SY-589 exhibits highly potent microhomology-mediated end joining (MMEJ) inhibition with IC50 of 0.85 nM in nanoluciferase-based MMEJ reporter assay.
SY-589 (0.05-12.8 nM) induces pronounced cell cycle arrest at the S phase in BRCA2-deficient DLD1 cells.
SY-589 shows snergistic antitumor activity with Olaparib in BRCA2-deficient DLD1 cells, significantly enhances Olaparib-induced apoptosis, increasing the apoptotic cell population to 44.2% compared to the blank group (9.13%) and Olaparib monotherapy (17.47%).
SY-589 (0.5, 2.5, or 12.5 mg/kg) demonstrated in vivo synergistic antitumor efficacy.