SY-589

SY-589 is an orally active DNA polymerase Polθ helicase domain inhibitor ( IC₅₀ =2.29 nM) and DNA damage inducer. SY-589 inhibits the ATPase activity of the Polθ helicase domain and blocks the Polθ -mediated microhomology-mediated end joining ( MMEJ ) DNA repair pathway ( IC₅₀ =0.85 nM). SY-589 also induces the accumulation of DNA double-strand breaks by increasing γ-H2AX levels. SY-589 exerts antiproliferative effects on BRCA2-deficient cells and is used in the research of HR-deficient tumors ^[1].

In Vivo, SY-589 (0.5-30 mg/kg; p.o.; daily; 27 d) inhibits tumor growth in the DLD1BRCA2-/- xenograft model; when combined with low-dose Olaparib, the tumor growth inhibition (TGI) rate reaches up to 109% with no significant toxicity^[1].

In Vitro, SY-589 (administered on days 0, 3, and 6) potently inhibits the viability of homologous recombination-deficient DLD1 BRCA2-/- colon cancer cells, with an IC₅₀ of 2.71 nM^[1]. SY-589 (0.05-12.8 nM; 10 d) induces dose-dependent accumulation of DNA double-strand breaks (detected by γ-H2AX levels) in DLD1 BRCA2-/- cells, and exerts dose-dependent effects on inhibiting colony formation, inducing cell cycle arrest and triggering apoptosis in DLD1 BRCA2-/- cells^[1]. SY-589 (0.39-100 nM; 10 d) exerts strong synergistic effects with the PARP inhibitor Olaparib to inhibit the viability of DLD1 BRCA2-/- cells, and significantly enhances the antiproliferative activity of Olaparib^[1].

References:
[1]. Ge C, et al. Discovery of SY-589, a Highly Potent and Orally Bioavailable Polθ Helicase Inhibitor for the Treatment of HR-Deficient Tumors. J Med Chem. 2026;69(3):2789-2813.