Ovarian cancer patients with HR proficiency (HRP) have had limited benefits from PARP inhibitor treatment, highlighting the need for improved therapeutic strategies. In this study, we developed a novel SIK2 inhibitor, SIC-19, and investigated its potential to enhance the sensitivity and expand the clinical utility of PARP inhibitors in ovarian cancer. The SIK2 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 20 candidate compounds were tested for their interaction with SIK2 and downstream substrates, AKT-pS473 and MYLK-pS343. SIC-19 emerged as the most promising drug candidate and was further evaluated using multiple assays. SIC-19 exhibited selective and potent inhibition of SIK2, leading to its degradation through the ubiquitination pathway. The IC50 of SIC-19 correlated inversely with endogenous SIK2 expression in ovarian cancer cell lines. Treatment with SIC-19 significantly inhibited cancer cell growth and sensitized cells to PARP inhibitors in vitro, as well as in ovarian cancer organoids and xenograft models. Mechanistically, SIK2 knockdown and SIC-19 treatment reduced RAD50 phosphorylation at Ser635, prevented nuclear translocation of RAD50, disrupted nuclear filament assembly, and impaired DNA homologous recombination repair, ultimately inducing apoptosis. These findings highlight the crucial role of SIK2 in the DNA HR repair pathway and demonstrate the significant PARP inhibitor sensitization achieved by SIC-19 in ovarian cancer. SIC-19, a novel SIK2 inhibitor, effectively inhibits tumor cell growth in ovarian cancer by interfering with RAD50-mediated DNA HR repair. Furthermore, SIC-19 enhances the efficacy of PARP inhibitors, providing a promising therapeutic strategy to improve outcomes for ovarian cancer patients.

中文翻译：

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新型 SIK2 抑制剂 SIC-19 在卵巢癌中与 PARP 抑制剂表现出合成致死作用

具有 HR 能力 (HRP) 的卵巢癌患者从 PARP 抑制剂治疗中获益有限，这凸显了改进治疗策略的必要性。在这项研究中，我们开发了一种新型 SIK2 抑制剂 SIC-19，并研究了其增强 PARP 抑制剂在卵巢癌中的敏感性和扩大临床应用的潜力。 SIK2 蛋白使用分子操作环境 (MOE) 进行建模，并根据 GBVI/WSA dG 评分函数选择最有利的模型。对 Chembridge 化合物库进行了筛选，并测试了前 20 种候选化合物与 SIK2 和下游底物 AKT-pS473 和 MYLK-pS343 的相互作用。 SIC-19 成为最有前途的候选药物，并使用多种测定法进行了进一步评估。 SIC-19 对 SIK2 表现出选择性和有效的抑制作用，导致其通过泛素化途径降解。 SIC-19 的 IC50 与卵巢癌细胞系中内源性 SIK2 表达呈负相关。在体外以及卵巢癌类器官和异种移植模型中，SIC-19 治疗可显着抑制癌细胞生长并使细胞对 PARP 抑制剂敏感。从机制上讲，SIK2 敲低和 SIC-19 治疗可降低 RAD50 Ser635 磷酸化，防止 RAD50 核转位，破坏核丝组装，并损害 DNA 同源重组修复，最终诱导细胞凋亡。这些发现强调了 SIK2 在 DNA HR 修复途径中的关键作用，并证明了 SIC-19 在卵巢癌中实现了显着的 PARP 抑制剂致敏作用。 SIC-19 是一种新型 SIK2 抑制剂，通过干扰 RAD50 介导的 DNA HR 修复，有效抑制卵巢癌中肿瘤细胞的生长。此外，SIC-19 增强了 PARP 抑制剂的功效，为改善卵巢癌患者的预后提供了一种有前途的治疗策略。