The novel PARP inhibitor no. 123 induces DNA damage and activates cGAS-STING signaling to suppress cervical cancer

Compound No. 123, a novel PARP inhibitor derived from thiosemicarbazone dimers, was investigated for its antitumor activity against cervical cancer and its ability to modulate antitumor immunity via the cGAS-STING pathway. No. 123 potently inhibited PARP1 enzymatic activity (IC 50 = 73.18 ± 12.04 nM) and showed a computationally predicted binding mode within the PARP1 catalytic domain through multiple interactions with key residues including ASP-807, GLN-717, LYS-893, GLU-809, and ILE-879. In HeLa cells, No. 123 suppressed proliferation by inducing G2/M phase arrest and triggered mitochondrial-mediated apoptosis through ROS generation and modulation of the Bax/Bcl-2 ratio. Importantly, No. 123 induced DNA damage, as evidenced by increased γH2AX expression, leading to activation of the cGAS-STING pathway, as evidenced by increased phosphorylation of STING, TBK1, and IRF3. In a murine cervical cancer model, oral administration of No. 123 significantly suppressed tumor growth (inhibition rate: 92%) and modulated antitumor immunity, as evidenced by increased dendritic cell maturation and altered tumor-infiltrating immune cell composition. In vivo mechanistic studies confirmed that No. 123 induced DNA damage (increased γH2AX expression) and activated the cGAS-STING pathway, leading to upregulated expression of downstream inflammatory cytokines in tumor tissues. Notably, No. 123 exhibited a favorable safety profile with no apparent organ toxicity or alterations in serum ALT/AST levels. These findings establish No. 123 as a promising therapeutic candidate for cervical cancer that exerts antitumor effects through a dual mechanism involving direct cytotoxicity and cGAS-STING-mediated immune activation, independent of canonical HRD/BRCA mutations.