Targeting MYC promoter G-quadruplex for MYC inhibition by Indenoisoquinolines

茚并异喹啉靶向 MYC 启动子 G-四链体抑制 MYC

基本信息

批准号：
10627757
负责人：
Herman O Sintim
金额：
$ 38.14万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627757
关键词：
Affinity Antineoplastic Agents Binding Biological Biological Assay Cellular Assay Clinical Complex DNA DNA-Protein Interaction Data Development Docking Drug Targeting Enzyme-Linked Immunosorbent Assay Fluorescence Resonance Energy Transfer Future G-Quartets Gene Expression Genes Genetic Transcription Goals Human In Vitro Lead Libraries Luciferases MYC Family Protein MYC gene Malignant Neoplasms Molecular Molecular Target Outcome Pharmaceutical Preparations Positioning Attribute Preclinical Testing Property Proteins Quantitative Reverse Transcriptase PCR Reporter Repression Research Small Interfering RNA Structure Structure-Activity Relationship Testing Topoisomerase Inhibitors Transcriptional Activation Transcriptional Silencer Elements Work analog biophysical techniques cancer cell design drug action functional group helicase improved in vivo inhibitor insight meter novel novel anticancer drug promoter rational design scaffold screening small molecule targeted treatment

项目摘要

PROJECT SUMMARY Targeting MYC promoter G-quadruplex for MYC inhibition by Indenoisoquinolines G-quadruplex (G4) DNA is a globular DNA secondary structure and considered as a new class of molecular targets for anticancer drugs. MYC, one of the most commonly deregulated genes in human cancers, has a DNA G4 motif in its promoter that functions as a transcriptional silencer. Compounds that bind to and stabilize the G-quadruplex formed in the MYC promoter have been shown to significantly lower MYC levels in cancer cells. Thus, the MYC promoter G-quadruplex (MycG4) represents a novel target for MYC inhibition by small molecules. However, little is known about how MycG4 is regulated by proteins and development of MycG4- targeting drugs has been focused solely on G4 DNA. Whereas drug-DNA interactions may be insufficient for MYC inhibition, the effective mechanism of drug action could involve protein-DNA interactions, which is analogous to topoisomerase inhibitors. Very recently, we have discovered that indenoisoquinolines, a clinically tested scaffold with excellent drug-like properties, are strong MycG4 binders and potent MYC inhibitors. We have also discovered that the DDX5 helicase actively unfolds MycG4 and is critically involved in MYC gene transcriptional activation. These results provide new and critical insights to effectively downregulate MYC transcription by targeting MycG4 and its interactions with DDX5. Our central hypothesis is that indenoisoquinolines effectively suppress MYC transcription by binding to the MYC promoter G-quadruplex and disrupting DDX5-MycG4 interactions. The overall objective is to determine the molecular mechanism of effective MYC inhibition by indenoisoquinolines, establish the structure–activity relationships (SAR), and discover lead indenoisoquinolines for preclinical testing. The long-term research goal is to develop potent indenoisoquinoline MYC inhibitors as new anticancer drugs. The specific aims are: 1) Structural characterization of the MycG4-indenoisoquinoline complexes. 2) Establishing a compound library to determine indenoisoquinolines that bind MycG4 and inhibit MYC. 3) Determining the effect of MycG4-interactive indenoisoquinolines on DDX5 unfolding of the MYC promoter G4 and how this correlates with MYC suppression. 4) Designing and synthesizing optimized indenoisoquinolines for MYC suppression using structure-based rational approach; establishing SAR for MycG4-binding and inhibition of DDX5 unfolding. The expected outcome of this work is a determination of the SAR of indenoisoquinolines for MycG4-targeting, demonstration of the effective MYC suppression by inhibiting DDX5-MycG4 interaction, and discovery of lead compounds for future preclinical testing. The results will have an important positive impact because they lay the groundwork to develop new indenoisoquinoline anticancer drugs with MYC-targeted activity.

项目摘要靶向MYC启动子G-四方链体以indenoisoquinolines抑制MYC G-四链体（G4）DNA是一个球状DNA二级结构，被认为是新的分子抗癌药物的靶标。 MYC是人类癌症中最常见的基因之一，有一个启动子中的DNA G4基序充当转录消音器。结合并稳定的化合物在MYC启动子中形成的G四链体已显示出明显降低癌症的MYC水平细胞。那就是MYC启动子G Quadruplex（mycg4）代表了小型MYC抑制的新目标分子。但是，关于MyCG4如何受到蛋白质的调节和Mycg4-的发展知之甚少靶向药物仅专注于G4 DNA。而药物-DNA相互作用可能不足 MYC抑制作用，药物作用的有效机制可能涉及蛋白-DNA相互作用，即类似于拓扑异构酶抑制剂。最近，我们发现临床上是Indenoisoquinolines 具有出色药物样特性的经过测试的支架是强大的mycg4粘合剂和潜在的MYC抑制剂。我们还发现DDX5解旋酶积极展开mycg4，并且与MYC基因非常重要转录激活。这些结果提供了有效下调MYC的新的和关键的见解通过靶向mycg4及其与DDX5的相互作用来转录。我们的中心假设是 indenoisoquinolines通过与MYC启动子G Quadruplex和破坏DDX5-MYCG4相互作用。总体目的是确定通过indenoisoquinolines抑制MYC，建立结构 - 活动关系（SAR）和发现用于临床前测试的铅Indenoisoquinolines。长期研究目标是发展有效 indenoisoquinoline myc抑制剂作为新的抗癌药。具体目的是：1）结构 mycg4- indenoisoquinoline复合物的表征。 2）建立一个复合库来确定结合mycg4并抑制MYC的indenoisoquinolines。 3）确定mycg4相互作用的效果 MYC启动子G4的DDX5上的Indenoisoquinolines以及MYC的相关性抑制。 4）设计和合成优化的Indenoisoquinolines，用于MYC抑制基于结构的理性方法；建立MYCG4结合和抑制DDX5展开的SAR。这这项工作的预期结果是确定mycg4靶向的indenoisoquinolines的SAR，通过抑制DDX5-MYCG4相互作用并发现铅来证明有效的MYC抑制未来临床前测试的化合物。结果将产生重要的积极影响，因为它们会产生开发具有MYC靶向活性的新的Indenoisoquinoline抗癌药物的基础。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

DNA Recognition by a Novel Bis-Intercalator, Potent Anticancer Drug XR5944.

DOI：
10.2174/1568026615666150413155608
发表时间：
2015
期刊：
Current topics in medicinal chemistry
影响因子：
3.4
作者：
Lin C;Yang D
通讯作者：
Yang D

A New G-Quadruplex with Hairpin Loop Immediately Upstream of the Human BCL2 P1 Promoter Modulates Transcription.

DOI：
10.1021/jacs.5b08596
发表时间：
2016-03-02
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Onel B;Carver M;Wu G;Timonina D;Kalarn S;Larriva M;Yang D
通讯作者：
Yang D

Human Telomeric G-Quadruplex Structures and G-Quadruplex-Interactive Compounds.

DOI：
10.1007/978-1-4939-6892-3_17
发表时间：
2017
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Lin C;Yang D
通讯作者：
Yang D

Selective lighting up of epiberberine alkaloid fluorescence by fluorophore-switching aptamer and stoichiometric targeting of human telomeric DNA G-quadruplex multimer.

DOI：
10.1021/ac503730j
发表时间：
2015-01-06
期刊：
Analytical chemistry
影响因子：
7.4
作者：
Zhang L;Liu H;Shao Y;Lin C;Jia H;Chen G;Yang D;Wang Y
通讯作者：
Wang Y

HMGB1 binds to the KRAS promoter G-quadruplex: a new player in oncogene transcriptional regulation?

DOI：
10.1039/c8cc03614d
发表时间：
2018-08-21
期刊：
Chemical communications (Cambridge, England)
影响因子：
0
作者：
Amato J ;Madanayake TW ;Iaccarino N ;Novellino E ;Randazzo A ;Hurley LH ;Pagano B
通讯作者：
Pagano B