Abstract 1478: A novel HK2 inhibitor HIC-29 exhibits synthetic lethality with PARP inhibitors in ovarian cancer

Abstract Purpose: In this study, we developed a novel HK2 inhibitor, HIC-29, and investigated its potential to enhance the sensitivity and expand the clinical utility of PARP inhibitors in ovarian cancer. Methods: The HK2 protein was modeled using a Molecular Operating Environment (MOE), and the most favorable model was selected based on a GBVI/WSA dG scoring function. The Chembridge Compound Library was screened, and the top 50 candidate compounds were tested for their interaction with HK2 and downstream substrates, CHK2-pS19 . HIC-29 emerged as the most promising drug candidate and was further evaluated using multiple assays. Results: HIC-29 exhibited selective and potent inhibition of HK2. The IC50 of HIC-29 correlated inversely with endogenous HK2 expression in ovarian cancer cell lines. Treatment with HIC-29 significantly inhibited cancer cell growth and sensitized cells to PARP inhibitors in vitro, as well as in ovarian cancer organoids and xenograft models. Mechanistically, HK2 knockdown and HIC-29 treatment reduced CHK2 phosphorylation at Ser19, impaired DNA homologous recombination repair, ultimately inducing apoptosis. These findings highlight the crucial role of HK2 in the DNA HR repair pathway and demonstrate the significant PARP inhibitor sensitization achieved by HIC-29 in ovarian cancer. Conclusions: HIC-29, a novel HK2 inhibitor, effectively inhibits tumor cell growth in ovarian cancer by interfering with CHK2-mediated DNA HR repair. Furthermore, HIC-29 enhances the efficacy of PARP inhibitors, providing a promising therapeutic strategy to improve outcomes for ovarian cancer patients. Citation Format: Xiu Shi. A novel HK2 inhibitor HIC-29 exhibits synthetic lethality with PARP inhibitors in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1478.