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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（由申请人提供）

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