A novel SIK2 inhibitor SIC-19 exhibits synthetic lethality with PARP inhibitors in ovarian cancer

IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Drug Resistance Updates Pub Date : 2024-03-06 DOI:10.1016/j.drup.2024.101077
Fang Wang , Xuejiao Yu , Jun Qian , Yumin Cao , Shunli Dong , Shenghua Zhan , Zhen Lu , Robert C. Bast Jr. , Qingxia Song , Youguo Chen , Yi Zhang , Jinhua Zhou
{"title":"A novel SIK2 inhibitor SIC-19 exhibits synthetic lethality with PARP inhibitors in ovarian cancer","authors":"Fang Wang ,&nbsp;Xuejiao Yu ,&nbsp;Jun Qian ,&nbsp;Yumin Cao ,&nbsp;Shunli Dong ,&nbsp;Shenghua Zhan ,&nbsp;Zhen Lu ,&nbsp;Robert C. Bast Jr. ,&nbsp;Qingxia Song ,&nbsp;Youguo Chen ,&nbsp;Yi Zhang ,&nbsp;Jinhua Zhou","doi":"10.1016/j.drup.2024.101077","DOIUrl":null,"url":null,"abstract":"<div><h3>Purpose</h3><p>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.</p></div><div><h3>Methods</h3><p>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.</p></div><div><h3>Results</h3><p>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.</p></div><div><h3>Conclusions</h3><p>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.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":15.8000,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1368764624000359/pdfft?md5=3ded3af8f90b410c4ce7fadd0299ea30&pid=1-s2.0-S1368764624000359-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Resistance Updates","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1368764624000359","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
新型 SIK2 抑制剂 SIC-19 与 PARP 抑制剂在卵巢癌中表现出合成致死性
HR熟练(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,并研究了它在提高 PARP 抑制剂对卵巢癌的敏感性和扩大其临床用途方面的潜力。我们使用分子操作环境(MOE)对 SIK2 蛋白进行了建模,并根据 GBVI/WSA dG 评分函数选择了最有利的模型。筛选了Chembridge化合物库,并测试了前20种候选化合物与SIK2及下游底物AKT-pS473和MYLK-pS343的相互作用。SIC-19 成为最有希望的候选药物,并通过多种检测方法进行了进一步评估。SIC-19 对 SIK2 具有选择性的强效抑制作用,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 的表达成反比。在体外以及卵巢癌器官组织和异种移植模型中,用SIC-19治疗可明显抑制癌细胞生长,并使细胞对PARP抑制剂敏感。从机理上讲,SIK2敲除和SIC-19处理降低了RAD50在Ser635处的磷酸化,阻止了RAD50的核转位,破坏了核丝组装,损害了DNA同源重组修复,最终诱导了细胞凋亡。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 在卵巢癌中对 PARP 抑制剂的显著增敏作用。新型 SIK2 抑制剂 SIC-19 通过干扰 RAD50 介导的 DNA HR 修复,有效抑制了卵巢癌肿瘤细胞的生长。此外,SIC-19 还能增强 PARP 抑制剂的疗效,为改善卵巢癌患者的预后提供了一种很有前景的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Drug Resistance Updates
Drug Resistance Updates 医学-药学
CiteScore
26.20
自引率
11.90%
发文量
32
审稿时长
29 days
期刊介绍: Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research
期刊最新文献
Targeting NQO1 induces ferroptosis and triggers anti-tumor immunity in immunotherapy-resistant KEAP1-deficient cancers Fasting-mimicking diet potentiates anti-tumor effects of CDK4/6 inhibitors against breast cancer by suppressing NRAS- and IGF1-mediated mTORC1 signaling Comprehensive metabolomic analysis identifies key biomarkers and modulators of immunotherapy response in NSCLC patients Novel mobile colistin resistance gene mcr-4.9 in Vibrio cholerae from migratory birds Acetate utilization promotes hormone therapy resistance in prostate cancer through neuroendocrine differentiation
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1