通过 DNAi 稳定 G-四链体靶向下调 MYC。

Targeted Downregulation of MYC through G-quadruplex Stabilization by DNAi.

机构信息

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY 13902, USA.

Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA.

出版信息

Molecules. 2021 Sep 13;26(18):5542. doi: 10.3390/molecules26185542.

DOI:10.3390/molecules26185542

PMID:34577013

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8464964/

Abstract

Modulating the expression or function of the enigmatic MYC protein has demonstrated efficacy in an array of cancer types and a marked potential therapeutic index and safety profile. Despite its high therapeutic value, specific and selective inhibitors or downregulating therapeutics have proven difficult to develop. In the current study, we expanded our work on a MYC promoter G-quadruplex (G4) stabilizing DNA clamp to develop an oligonucleotide interfering DNA (DNAi) therapeutic. We explored six DNAi for G4-stabilization through EMSA, DMS footprinting, and thermal stability studies, focusing on the DNAi 5T as the lead therapeutic. 5T, but not its scramble control 5Tscr, was then shown to enter the nucleus, modulate cell viability, and decrease MYC expression through G4-stabilization. DNAi 5T is thus described to be our lead DNAi, targeting MYC regulation through stabilization of the higher-order DNA G4 structure in the proximal promoter, and it is poised for further preclinical development as an anticancer therapeutic.

摘要

调节神秘的 MYC 蛋白的表达或功能已在多种癌症类型中显示出疗效，且具有显著的治疗指数和安全性。尽管其具有很高的治疗价值，但特异性和选择性抑制剂或下调治疗药物的开发一直很困难。在本研究中，我们扩展了我们在 MYC 启动子 G-四链体（G4）稳定 DNA 夹上的工作，以开发一种寡核苷酸干扰 DNA（DNAi）治疗药物。我们通过 EMSA、DMS 足迹和热稳定性研究探索了六种用于 G4 稳定的 DNAi，重点关注 DNAi 5T 作为先导治疗药物。结果表明，5T 而不是其乱序对照 5Tscr 能够进入细胞核，通过 G4 稳定调节细胞活力并降低 MYC 表达。因此，DNAi 5T 被描述为我们的先导 DNAi，通过稳定近端启动子中的高级 DNA G4 结构来靶向 MYC 调节，并且有望进一步作为抗癌治疗药物进行临床前开发。