Suppr超能文献

鉴定和评估一种新型 PARP1 抑制剂用于治疗三阴性乳腺癌。

Identification and evaluation of a novel PARP1 inhibitor for the treatment of triple-negative breast cancer.

机构信息

Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China; Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, China.

Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China.

出版信息

Chem Biol Interact. 2023 Sep 1;382:110567. doi: 10.1016/j.cbi.2023.110567. Epub 2023 Jun 2.

Abstract

Triple-negative breast cancer (TNBC) is a particularly invasive subtype of breast cancer and usually has a poor prognosis due to the lack of effective therapeutic targets. Approximately 25% of TNBC patients carry a breast cancer susceptibility gene1/2 (BRCA1/2) mutation. Clinically, PARP1 inhibitors have been approved for the treatment of patients with BRCA1/2-mutated breast cancer through the mechanism of synthetic lethality. In this study, we identified compound 6 {systematic name: 2-[2-(4-Hydroxy-phenyl)-vinyl]-3H-quinazolin-4-one} as a novel PARP1 inhibitor from established virtual screening methods. Compound 6 exerted stronger PARP1 inhibitory activity and anti-cancer activity as compared to olaparib in BRCA1-mutated TNBC cells and TNBC patient-derived organoids. Unexpectedly, we found that compound 6 also significantly inhibited cell viability, proliferation, and induced cell apoptosis in BRCA wild-type TNBC cells. To further elucidate the underlying molecular mechanism, we found that tankyrase (TNKS), a vital promoter of homologous-recombination repair, was a potential target of compound 6 by cheminformatics analysis. Compound 6 not only decreased the expression of PAR, but also down-regulated the expression of TNKS, thus resulting in significant DNA single-strand and double-strand breaks in BRCA wild-type TNBC cells. In addition, we demonstrated that compound 6 enhanced the sensitivity of BRCA1-mutated and wild-type TNBC cells to chemotherapy including paclitaxel and cisplatin. Collectively, our study identified a novel PARP1 inhibitor, providing a therapeutic candidate for the treatment of TNBC.

摘要

三阴性乳腺癌(TNBC)是一种侵袭性较强的乳腺癌亚型,由于缺乏有效的治疗靶点,通常预后较差。大约 25%的 TNBC 患者携带乳腺癌易感基因 1/2(BRCA1/2)突变。临床上,通过合成致死的机制,PARP1 抑制剂已被批准用于治疗携带 BRCA1/2 突变的乳腺癌患者。在这项研究中,我们从已建立的虚拟筛选方法中鉴定出化合物 6(系统命名:2-[2-(4-羟基苯基)-乙烯基]-3H-喹唑啉-4-酮)为一种新型的 PARP1 抑制剂。与奥拉帕利相比,化合物 6 在 BRCA1 突变的 TNBC 细胞和 TNBC 患者来源的类器官中表现出更强的 PARP1 抑制活性和抗癌活性。出乎意料的是,我们发现化合物 6 还能显著抑制 BRCA 野生型 TNBC 细胞的活力、增殖,并诱导细胞凋亡。为了进一步阐明潜在的分子机制,我们通过化学信息学分析发现,tankyrase(TNKS),同源重组修复的重要启动子,是化合物 6 的一个潜在靶点。化合物 6 不仅降低了 PAR 的表达,还下调了 TNKS 的表达,从而导致 BRCA 野生型 TNBC 细胞中出现明显的 DNA 单链和双链断裂。此外,我们证明化合物 6 增强了 BRCA1 突变型和野生型 TNBC 细胞对包括紫杉醇和顺铂在内的化疗药物的敏感性。总之,我们的研究鉴定出一种新型的 PARP1 抑制剂,为治疗 TNBC 提供了一种治疗候选药物。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验