一种具有抗癌活性的针对 RNA 聚合酶 I 的靶向破坏方式。
A targeting modality for destruction of RNA polymerase I that possesses anticancer activity.
机构信息
Molecular Cancer Biology Program and Centre for Drug Research, University of Helsinki, Helsinki 00014, Finland.
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
出版信息
Cancer Cell. 2014 Jan 13;25(1):77-90. doi: 10.1016/j.ccr.2013.12.009.
Abstract
We define the activity and mechanisms of action of a small molecule lead compound for cancer targeting. We show that the compound, BMH-21, has wide and potent antitumorigenic activity across NCI60 cancer cell lines and represses tumor growth in vivo. BMH-21 binds GC-rich sequences, which are present at a high frequency in ribosomal DNA genes, and potently and rapidly represses RNA polymerase I (Pol I) transcription. Strikingly, we find that BMH-21 causes proteasome-dependent destruction of RPA194, the large catalytic subunit protein of Pol I holocomplex, and this correlates with cancer cell killing. Our results show that Pol I activity is under proteasome-mediated control, which reveals an unexpected therapeutic opportunity.
摘要
我们定义了一种用于癌症靶向的小分子先导化合物的活性和作用机制。我们表明，该化合物 BMH-21 在 NCI60 癌细胞系中具有广泛而有效的抗肿瘤活性，并在体内抑制肿瘤生长。BMH-21 结合富含 GC 的序列，这些序列在核糖体 DNA 基因中高频出现，并强烈且快速地抑制 RNA 聚合酶 I（Pol I）转录。引人注目的是，我们发现 BMH-21 导致蛋白酶体依赖性破坏 RPA194，即 Pol I 全酶复合物的大亚基蛋白，这与癌细胞杀伤相关。我们的结果表明，Pol I 活性受到蛋白酶体介导的控制，这揭示了一个意外的治疗机会。
相似文献
1
A targeting modality for destruction of RNA polymerase I that possesses anticancer activity.一种具有抗癌活性的针对 RNA 聚合酶 I 的靶向破坏方式。
Cancer Cell. 2014 Jan 13;25(1):77-90. doi: 10.1016/j.ccr.2013.12.009.
2
Small molecule BMH-compounds that inhibit RNA polymerase I and cause nucleolar stress.抑制RNA聚合酶I并引起核仁应激的小分子BMH化合物。
Mol Cancer Ther. 2014 Nov;13(11):2537-46. doi: 10.1158/1535-7163.MCT-14-0256. Epub 2014 Oct 2.
3
Design, synthesis, and structure-activity relationships of pyridoquinazolinecarboxamides as RNA polymerase I inhibitors.设计、合成及吡啶并喹唑啉甲酰胺类 RNA 聚合酶 I 抑制剂的构效关系研究。
J Med Chem. 2014 Jun 12;57(11):4950-61. doi: 10.1021/jm5004842. Epub 2014 May 30.
4
Effective targeting of RNA polymerase I in treatment-resistant prostate cancer.针对耐药性前列腺癌的 RNA 聚合酶 I 的有效靶向治疗。
Prostate. 2019 Dec;79(16):1837-1851. doi: 10.1002/pros.23909. Epub 2019 Sep 16.
5
Targeting RNA polymerase I transcription machinery in cancer cells by a novel monofunctional platinum-based agent.新型单功能铂类药物靶向癌细胞 RNA 聚合酶 I 转录机制。
Eur J Med Chem. 2018 Jul 15;155:434-444. doi: 10.1016/j.ejmech.2018.05.045. Epub 2018 Jun 1.
6
Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth.靶向 RNA 聚合酶 I 的口服小分子 CX-5461 抑制核糖体 RNA 合成和实体瘤生长。
Cancer Res. 2011 Feb 15;71(4):1418-30. doi: 10.1158/0008-5472.CAN-10-1728. Epub 2010 Dec 15.
7
Targeting ribosomal G-quadruplexes with naphthalene-diimides as RNA polymerase I inhibitors for colorectal cancer treatment.用萘二酰亚胺靶向核糖体 G-四链体作为 RNA 聚合酶 I 抑制剂治疗结直肠癌。
Cell Chem Biol. 2021 Nov 18;28(11):1590-1601.e4. doi: 10.1016/j.chembiol.2021.05.021. Epub 2021 Jun 23.
8
Discovery of a novel dipeptidyl boronic acid proteasome inhibitor for the treatment of multiple myeloma and triple-negative breast cancer.新型二肽硼酸蛋白酶体抑制剂的发现及其在多发性骨髓瘤和三阴性乳腺癌治疗中的应用。
Org Biomol Chem. 2019 Jan 16;17(3):683-691. doi: 10.1039/c8ob02668h.
9
Expression of RNA polymerase I catalytic core is influenced by RPA12.RNA 聚合酶 I 催化核心的表达受 RPA12 的影响。
PLoS One. 2023 May 11;18(5):e0285660. doi: 10.1371/journal.pone.0285660. eCollection 2023.
10
Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells.鲁比卡丁特异性触发癌细胞中磷酸化RNA聚合酶II的降解和DNA断裂的形成。
Mol Cancer Ther. 2016 Oct;15(10):2399-2412. doi: 10.1158/1535-7163.MCT-16-0172. Epub 2016 Sep 14.
引用本文的文献
1
Hypoxic stress incites HIF1α-driven ribosome biogenesis that can be exploited by targeting RNA Polymerase I.缺氧应激会引发由缺氧诱导因子1α（HIF1α）驱动的核糖体生物合成，这一过程可通过靶向RNA聚合酶I来加以利用。
Nat Commun. 2025 Aug 27;16(1):8018. doi: 10.1038/s41467-025-63315-3.
2
Atypical R-loops in cancer: decoding molecular chaos for therapeutic gain.癌症中的非典型R环：破解分子混乱以实现治疗效益。
J Transl Med. 2025 Aug 14;23(1):912. doi: 10.1186/s12967-025-06929-x.
3
Precise mapping of single-stranded DNA breaks by sequence-templated erroneous DNA polymerase end-labelling.通过序列模板化错误DNA聚合酶末端标记对单链DNA断裂进行精确映射。
Nat Commun. 2025 Aug 4;16(1):7130. doi: 10.1038/s41467-025-62512-4.
4
Anticancer drug development against ribosome synthesis and the nucleolus.针对核糖体合成及核仁的抗癌药物研发
Biochem Soc Trans. 2025 Aug 4. doi: 10.1042/BST20253011.
5
Elevated NPM1 and FBL expression correlates with prostate cancer aggressiveness and progression.NPM1和FBL表达升高与前列腺癌的侵袭性和进展相关。
J Pathol. 2025 Sep;267(1):56-68. doi: 10.1002/path.6447. Epub 2025 Jul 24.
6
Ribosomal RNA transcription regulates splicing through ribosomal protein RPL22.核糖体RNA转录通过核糖体蛋白RPL22调节剪接。
Cell Chem Biol. 2025 Jul 17;32(7):908-925.e9. doi: 10.1016/j.chembiol.2025.05.012. Epub 2025 Jun 18.
7
Bypassing the guardian: regulated cell death pathways in p53-mutant cancers.绕过守护者：p53 突变型癌症中的程序性细胞死亡途径
Cell Mol Biol Lett. 2025 Jun 14;30(1):68. doi: 10.1186/s11658-025-00751-5.
8
4(3)-Quinazolinone: A Natural Scaffold for Drug and Agrochemical Discovery.4(3)-喹唑啉酮：药物与农用化学品研发的天然骨架
Int J Mol Sci. 2025 Mar 10;26(6):2473. doi: 10.3390/ijms26062473.
9
The natural alkaloid nitidine chloride targets RNA polymerase I to inhibit ribosome biogenesis and repress cancer cell growth.天然生物碱氯化两面针碱靶向RNA聚合酶I以抑制核糖体生物发生并抑制癌细胞生长。
Cell Death Discov. 2025 Mar 22;11(1):116. doi: 10.1038/s41420-025-02396-x.
10
Inhibition of Ribosome Biogenesis In Vivo Causes p53-Dependent Death and p53-Independent Dysfunction.体内核糖体生物合成的抑制导致p53依赖性死亡和p53非依赖性功能障碍。
Cell Mol Gastroenterol Hepatol. 2025;19(7):101496. doi: 10.1016/j.jcmgh.2025.101496. Epub 2025 Mar 11.
本文引用的文献
1
Dysregulation of the basal RNA polymerase transcription apparatus in cancer.癌症中基本 RNA 聚合酶转录装置的失调。
Nat Rev Cancer. 2013 May;13(5):299-314. doi: 10.1038/nrc3496.
2
Cancer genome landscapes.肿瘤基因组图谱。
Science. 2013 Mar 29;339(6127):1546-58. doi: 10.1126/science.1235122.
3
Ubiquitylation and degradation of elongating RNA polymerase II: the last resort.延伸中的RNA聚合酶II的泛素化与降解：最后的手段
Biochim Biophys Acta. 2013 Jan;1829(1):151-7. doi: 10.1016/j.bbagrm.2012.08.002. Epub 2012 Aug 31.
4
A conserved deubiquitinating enzyme controls cell growth by regulating RNA polymerase I stability.一种保守的去泛素化酶通过调控 RNA 聚合酶 I 的稳定性来控制细胞生长。
Cell Rep. 2012 Aug 30;2(2):372-85. doi: 10.1016/j.celrep.2012.07.009. Epub 2012 Aug 16.
5
Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53.抑制 RNA 聚合酶 I 作为一种促进 p53 肿瘤特异性激活的治疗策略。
Cancer Cell. 2012 Jul 10;22(1):51-65. doi: 10.1016/j.ccr.2012.05.019.
6
AKT promotes rRNA synthesis and cooperates with c-MYC to stimulate ribosome biogenesis in cancer.AKT 促进 rRNA 合成，并与 c-MYC 协同作用刺激癌症中的核糖体生物发生。
Sci Signal. 2011 Aug 30;4(188):ra56. doi: 10.1126/scisignal.2001754.
7
Curaxins: anticancer compounds that simultaneously suppress NF-κB and activate p53 by targeting FACT.Curaxins：通过靶向 FACT 同时抑制 NF-κB 并激活 p53 的抗癌化合物。
Sci Transl Med. 2011 Aug 10;3(95):95ra74. doi: 10.1126/scitranslmed.3002530.
8
Quantitative proteomics and dynamic imaging of the nucleolus reveal distinct responses to UV and ionizing radiation.定量蛋白质组学和核仁的动态成像揭示了对紫外线和电离辐射的不同反应。
Mol Cell Proteomics. 2011 Oct;10(10):M111.009241. doi: 10.1074/mcp.M111.009241. Epub 2011 Jul 21.
9
Establishment and maintenance of alternative chromatin states at a multicopy gene locus.在一个多拷贝基因座上建立和维持替代性染色质状态。
Cell. 2011 May 13;145(4):543-54. doi: 10.1016/j.cell.2011.03.051.
10
Nuclear ErbB2 enhances translation and cell growth by activating transcription of ribosomal RNA genes.核 ErbB2 通过激活核糖体 RNA 基因的转录来增强翻译和细胞生长。
Cancer Res. 2011 Jun 15;71(12):4269-79. doi: 10.1158/0008-5472.CAN-10-3504. Epub 2011 May 9.
Zotero 插件