Drugging the Undruggable: Targeting Transcription Factors with Small Cyclic Pept

对不可成药的药物进行药物治疗：用小环肽靶向转录因子

基本信息

批准号：
7981860
负责人：
Joshua A Kritzer
金额：
$ 230.25万
依托单位：
TUFTS UNIVERSITY MEDFORD
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2015-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (Provided by the applicant) Abstract: Drugging the Undruggable: Targeting Transcription Factors with Small Cyclic Peptides Transcription factors such as Myc, STAT3 and HSF1 represent key targets for novel cancer therapies. Because they lack the structural features of traditional drug targets, these proteins are often classified as "undruggable." This assumption is perpetuated by the fact that, despite intensive screening efforts using traditional methods, there are few known compounds that target transcription factors. However, potent natural products such as cyclosporine and rapamycin can bind diverse, non-traditional targets that would otherwise be overlooked. Cyclic peptides resemble these natural product macrocycles, and thus have the potential to target promising proteins, including transcription factors, previously dismissed as "undruggable." Novel screening technologies will be required to discover bioactive cyclic peptides (CPs). We recently described a method of genetically encoding CP libraries for phenotypic selections in the yeast Saccharomyces cerevisiae. Since transcription is such a fundamental process, it is critical to perform selections in live organisms to ensure activity and selectivity for the target protein in the context of the full eukaryotic transcriptional machinery. This technique allows tens of millions of CPs to be screened in live cells in a single day without expensive robotics, and provides a rapid route for secondary testing and optimization of hits. This proposal describes application of this method to discover CPs that inhibit diverse human transcription factors implicated in cancer. This will be accomplished by: (1) engineering yeast selection strains that report on protein-protein and protein-DNA interactions of Myc, STAT3 and HSF1, (2) applying CP libraries to the selection strains to isolate molecules that selectively disrupt these interactions, and (3) elucidating the mechanisms of action of the most promising CPs at the molecular and cellular level. These experiments will provide first-in-class drug leads suitable for further development, and will also demonstrate a rapid, inexpensive approach to drug discovery for previously overlooked targets. Public Health Relevance: Despite their fundamental roles in disease biology, transcription factors have been dismissed as "undruggable" due to their structural properties. This proposal outlines a general strategy for targeting these proteins for therapeutic intervention, and applies this strategy to diverse transcription factors that cause human cancer. Validation of these and other overlooked drug targets would be a true game-changer for drug development in every major disease field.

描述（申请人提供）摘要：吸毒不可能的：用小环状肽转录因子（例如MYC，STAT3和HSF1）靶向转录因子代表了新型癌症疗法的关键靶标。由于它们缺乏传统药物靶标的结构特征，因此这些蛋白质通常被归类为“不可用”。这一假设的持续了以下事实：尽管使用传统方法进行了密集的筛查工作，但靶向转录因子的已知化合物很少。但是，诸如环孢菌素和雷帕霉素之类的有效天然产物可以结合多样化的非传统靶标，否则会忽略这些目标。环状肽类似于这些天然产物大环，因此有可能靶向有前途的蛋白质，包括转录因子，以前被视为“不可用”。需要新的筛查技术来发现生物活性循环肽（CPS）。最近，我们描述了一种在酵母糖酵母中进行表型选择的遗传编码CP文库的方法。由于转录是一个基本过程，因此在全真核转录机械的背景下，在活有机体中进行选择以确保目标蛋白的活动和选择性至关重要。该技术允许在没有昂贵的机器人技术的情况下在活细胞中筛选数千万的CP，并为次要测试和命中优化提供了快速的途径。该提案描述了这种方法在发现抑制涉及癌症的各种人类转录因子的CP中的应用。这将通过：（1）报告蛋白质 - 蛋白质蛋白质和MYC，Stat3和HSF1的蛋白质DNA相互作用的工程酵母选择菌株，（2）将CP库应用于选择性菌株的分离分子，这些分子有选择地破坏这些相互作用，并阐明这些相互作用的相互作用，以及（3）阐明了最具前景的CPS和Cell Cell and cell and cons and cps and cps and comp and cps and cons and cps and cps and Morecular calt and Morecular。这些实验将提供适合进一步开发的一流药物铅，还将证明一种快速，廉价的药物发现方法，用于以前被忽视的靶标。公共卫生相关性：尽管它们在疾病生物学中的基本作用，但由于其结构特性，转录因素被视为“不可能”。该建议概述了针对这些蛋白质进行治疗干预的一般策略，并将此策略应用于导致人类癌症的各种转录因子。对这些和其他被忽视的药物靶标的验证将是每个主要疾病领域的药物开发的真正改变游戏规则。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Peptide bicycles that inhibit the Grb2 SH2 domain.

DOI：
10.1002/cbic.201200175
发表时间：
2012-07-09
期刊：
CHEMBIOCHEM
影响因子：
3.2
作者：
Quartararo, Justin S.;Wu, Pianpian;Kritzer, Joshua A.
通讯作者：
Kritzer, Joshua A.

Structured cyclic peptides that bind the EH domain of EHD1.

DOI：
10.1021/bi500744q
发表时间：
2014-07-29
期刊：
BIOCHEMISTRY
影响因子：
2.9
作者：
Kamens, Alissa J.;Eisert, Robyn J.;Corlin, Tiffany;Baleja, James D.;Kritzer, Joshua A.
通讯作者：
Kritzer, Joshua A.

A bicyclic peptide scaffold promotes phosphotyrosine mimicry and cellular uptake.

双环肽支架促进磷酸酪氨酸模拟和细胞摄取。

DOI：
10.1016/j.bmc.2014.09.050
发表时间：
2014
期刊：
Bioorganic & medicinal chemistry
影响因子：
3.5
作者：
Quartararo,JustinS;Eshelman,MatthewR;Peraro,Leila;Yu,Hongtao;Baleja,JamesD;Lin,Yu-Shan;Kritzer,JoshuaA
通讯作者：
Kritzer,JoshuaA