• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

靶向BRD4末端外结构域的肽抑制剂可有效抑制乳腺癌的生长和转移。

Peptide Inhibitor Targeting the Extraterminal Domain in BRD4 Potently Suppresses Breast Cancer Both and .

作者信息

Huang Qi-Xuan, Fan Da-Meng, Zheng Zao-Zao, Ran Ting, Bai Ao, Xiao Rong-Quan, Hu Guo-Sheng, Liu Wen

机构信息

State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China.

Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China.

出版信息

J Med Chem. 2024 Apr 25;67(8):6658-6672. doi: 10.1021/acs.jmedchem.4c00141. Epub 2024 Apr 3.

DOI:10.1021/acs.jmedchem.4c00141
PMID:38569135
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11056977/
Abstract

BRD4 is associated with a variety of human diseases, including breast cancer. The crucial roles of amino-terminal bromodomains (BDs) of BRD4 in binding with acetylated histones to regulate oncogene expression make them promising drug targets. However, adverse events impede the development of the BD inhibitors. BRD4 adopts an extraterminal (ET) domain, which recruits proteins to drive oncogene expression. We discovered a peptide inhibitor PiET targeting the ET domain to disrupt BRD4/JMJD6 interaction, a protein complex critical in oncogene expression and breast cancer. The cell-permeable form of PiET, TAT-PiET, and PROTAC-modified TAT-PiET, TAT-PiET-PROTAC, potently inhibits the expression of BRD4/JMJD6 target genes and breast cancer cell growth. Combination therapy with TAT-PiET/TAT-PiET-PROTAC and JQ1, iJMJD6, or Fulvestrant exhibits synergistic effects. TAT-PiET or TAT-PiET-PROTAC treatment overcomes endocrine therapy resistance in ERα-positive breast cancer cells. Taken together, we demonstrated that targeting the ET domain is effective in suppressing breast cancer, providing a therapeutic avenue in the clinic.

摘要

BRD4与多种人类疾病相关，包括乳腺癌。BRD4的氨基末端溴结构域（BDs）在与乙酰化组蛋白结合以调节癌基因表达方面的关键作用使其成为有前景的药物靶点。然而，不良事件阻碍了BD抑制剂的开发。BRD4采用一个额外末端（ET）结构域，该结构域招募蛋白质来驱动癌基因表达。我们发现了一种靶向ET结构域的肽抑制剂PiET，以破坏BRD4/JMJD6相互作用，这是一种在癌基因表达和乳腺癌中至关重要的蛋白质复合物。PiET的细胞可渗透形式TAT-PiET以及PROTAC修饰的TAT-PiET即TAT-PiET-PROTAC，可有效抑制BRD4/JMJD6靶基因的表达和乳腺癌细胞的生长。TAT-PiET/TAT-PiET-PROTAC与JQ1、iJMJD6或氟维司群联合治疗具有协同作用。TAT-PiET或TAT-PiET-PROTAC治疗克服了ERα阳性乳腺癌细胞中的内分泌治疗耐药性。综上所述，我们证明靶向ET结构域在抑制乳腺癌方面是有效的，为临床提供了一条治疗途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac3/11056977/3ca3b95821ec/jm4c00141_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac3/11056977/95baa4d3bcb0/jm4c00141_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac3/11056977/0f830d180e7f/jm4c00141_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac3/11056977/5b7788adf094/jm4c00141_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac3/11056977/ec696b42b72f/jm4c00141_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac3/11056977/11462a0cf7a0/jm4c00141_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac3/11056977/aae2503b369b/jm4c00141_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac3/11056977/3ca3b95821ec/jm4c00141_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac3/11056977/95baa4d3bcb0/jm4c00141_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac3/11056977/0f830d180e7f/jm4c00141_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac3/11056977/5b7788adf094/jm4c00141_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac3/11056977/ec696b42b72f/jm4c00141_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac3/11056977/11462a0cf7a0/jm4c00141_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac3/11056977/aae2503b369b/jm4c00141_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ac3/11056977/3ca3b95821ec/jm4c00141_0007.jpg

相似文献

1
Peptide Inhibitor Targeting the Extraterminal Domain in BRD4 Potently Suppresses Breast Cancer Both and .靶向BRD4末端外结构域的肽抑制剂可有效抑制乳腺癌的生长和转移。
J Med Chem. 2024 Apr 25;67(8):6658-6672. doi: 10.1021/acs.jmedchem.4c00141. Epub 2024 Apr 3.
2
BRD4-specific PROTAC inhibits basal-like breast cancer partially through downregulating KLF5 expression.BRD4 特异性 PROTAC 通过下调 KLF5 表达部分抑制基底样乳腺癌。
Oncogene. 2024 Sep;43(39):2914-2926. doi: 10.1038/s41388-024-03121-1. Epub 2024 Aug 20.
3
Design, synthesis, and antitumor evaluation of triazolopyridine derivatives as novel inhibitors for BRD4.作为新型BRD4抑制剂的三唑并吡啶衍生物的设计、合成及抗肿瘤评价
Eur J Med Chem. 2025 Mar 5;285:117272. doi: 10.1016/j.ejmech.2025.117272. Epub 2025 Jan 13.
4
Targeting Hippo coactivator YAP1 through BET bromodomain inhibition in esophageal adenocarcinoma.针对食管腺癌中的 Hippo 共激活因子 YAP1 通过 BET 溴结构域抑制。
Mol Oncol. 2020 Jun;14(6):1410-1426. doi: 10.1002/1878-0261.12667. Epub 2020 Apr 7.
5
Novel inhibitors of bromodomain and extra-terminal domain trigger cell death in breast cancer cell lines.新型溴结构域和末端外结构域抑制剂可诱导乳腺癌细胞系发生细胞死亡。
Bioorg Med Chem. 2024 Oct 1;112:117884. doi: 10.1016/j.bmc.2024.117884. Epub 2024 Aug 31.
6
Co-targeting BET bromodomain BRD4 and RAC1 suppresses growth, stemness and tumorigenesis by disrupting the c-MYC-G9a-FTH1axis and downregulating HDAC1 in molecular subtypes of breast cancer.靶向 BET 溴结构域蛋白 BRD4 和 RAC1 通过破坏 c-MYC-G9a-FTH1 轴和下调乳腺癌分子亚型中的 HDAC1 来抑制生长、干性和肿瘤发生。
Int J Biol Sci. 2021 Oct 25;17(15):4474-4492. doi: 10.7150/ijbs.62236. eCollection 2021.
7
AZD5153: A Novel Bivalent BET Bromodomain Inhibitor Highly Active against Hematologic Malignancies.AZD5153：一种新型双价 BET 溴结构域抑制剂，对血液系统恶性肿瘤具有高度活性。
Mol Cancer Ther. 2016 Nov;15(11):2563-2574. doi: 10.1158/1535-7163.MCT-16-0141. Epub 2016 Aug 29.
8
Combining Data-Driven and Structure-Based Approaches in Designing Dual PARP1-BRD4 Inhibitors for Breast Cancer Treatment.结合数据驱动和基于结构的方法设计用于治疗乳腺癌的双重 PARP1-BRD4 抑制剂。
J Chem Inf Model. 2024 Oct 14;64(19):7725-7742. doi: 10.1021/acs.jcim.4c01421. Epub 2024 Sep 18.
9
Bromodomain and extraterminal domain inhibitor enhances the antitumor effect of imatinib in gastrointestinal stromal tumours.溴结构域和末端外结构域抑制剂增强伊马替尼治疗胃肠道间质瘤的抗肿瘤作用。
J Cell Mol Med. 2020 Feb;24(4):2519-2530. doi: 10.1111/jcmm.14945. Epub 2020 Jan 19.
10
Discovery of a series of dihydroquinoxalin-2(1H)-ones as selective BET inhibitors from a dual PLK1-BRD4 inhibitor.从双重 PLK1-BRD4 抑制剂中发现一系列二氢喹喔啉-2(1H)-酮作为选择性 BET 抑制剂。
Eur J Med Chem. 2017 Sep 8;137:176-195. doi: 10.1016/j.ejmech.2017.05.049. Epub 2017 May 27.

引用本文的文献

1
A Minireview on BET Inhibitors: Beyond Bromodomain Targeting.BET抑制剂综述：超越溴结构域靶向作用
Biomedicines. 2025 Mar 1;13(3):594. doi: 10.3390/biomedicines13030594.
2
Identification of Novel Bromodomain-Containing Protein 4 (BRD4) Binders through 3D Pharmacophore-Based Repositioning Screening Campaign.通过基于 3D 药效团的重定位筛选活动鉴定新型溴结构域蛋白 4（BRD4）结合物。
Molecules. 2024 Aug 26;29(17):4025. doi: 10.3390/molecules29174025.

本文引用的文献

1
BET proteins: Biological functions and therapeutic interventions.BET 蛋白：生物学功能与治疗干预。
Pharmacol Ther. 2023 Mar;243:108354. doi: 10.1016/j.pharmthera.2023.108354. Epub 2023 Feb 3.
2
Targeting Breast Cancer Stem Cells.靶向乳腺癌干细胞。
Int J Biol Sci. 2023 Jan 1;19(2):552-570. doi: 10.7150/ijbs.76187. eCollection 2023.
3
JMJD6 orchestrates a transcriptional program in favor of endocrine resistance in ER+ breast cancer cells.JMJD6 调控有利于 ER+乳腺癌细胞内分泌抵抗的转录程序。
Front Endocrinol (Lausanne). 2022 Nov 7;13:1028616. doi: 10.3389/fendo.2022.1028616. eCollection 2022.
4
Super-enhancer-controlled positive feedback loop BRD4/ERα-RET-ERα promotes ERα-positive breast cancer.超级增强子控制的正反馈回路 BRD4/ERα-RET-ERα 促进了 ERα 阳性乳腺癌的发生。
Nucleic Acids Res. 2022 Oct 14;50(18):10230-10248. doi: 10.1093/nar/gkac778.
5
A specific JMJD6 inhibitor potently suppresses multiple types of cancers both in vitro and in vivo.一种特定的 JMJD6 抑制剂在体外和体内均能强效抑制多种类型的癌症。
Proc Natl Acad Sci U S A. 2022 Aug 23;119(34):e2200753119. doi: 10.1073/pnas.2200753119. Epub 2022 Aug 15.
6
A Comprehensive Review of BET Protein Biochemistry, Physiology, and Pathological Roles.BET蛋白的生物化学、生理学及病理作用综述
Front Pharmacol. 2022 Mar 25;13:818891. doi: 10.3389/fphar.2022.818891. eCollection 2022.
7
Development of Murine Leukemia Virus Integrase-Derived Peptides That Bind Brd4 Extra-Terminal Domain as Candidates for Suppression of Acute Myeloid Leukemia.作为抑制急性髓系白血病候选药物的、与溴结构域蛋白4额外末端结构域结合的鼠白血病病毒整合酶衍生肽的研发。
ACS Pharmacol Transl Sci. 2021 Sep 10;4(5):1628-1638. doi: 10.1021/acsptsci.1c00159. eCollection 2021 Oct 8.
8
Oncogenic Truncations of ASXL1 Enhance a Motif for BRD4 ET-Domain Binding.ASXL1的致癌性截短增强了与BRD4 ET结构域结合的基序。
J Mol Biol. 2021 Nov 5;433(22):167242. doi: 10.1016/j.jmb.2021.167242. Epub 2021 Sep 15.
9
ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer.ASXL3 桥接 BRD4 与 BAP1 复合物并调控小细胞肺癌中的增强子活性。
Genome Med. 2020 Jul 15;12(1):63. doi: 10.1186/s13073-020-00760-3.
10
Overcoming Endocrine Resistance in Breast Cancer.克服乳腺癌内分泌耐药。
Cancer Cell. 2020 Apr 13;37(4):496-513. doi: 10.1016/j.ccell.2020.03.009.