Targeting the Oncogenic Fusion Transcription Factor PAX3-FOXO1 with Small Molecules
用小分子靶向致癌融合转录因子 PAX3-FOXO1
基本信息
- 批准号:10372971
- 负责人:
- 金额:$ 1.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2022-05-06
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAffinityAlveolar RhabdomyosarcomaBindingBinding SitesBiologicalBiological AssayBiologyBiophysicsCancer BiologyCell DeathCell Differentiation processCellsChemicalsChimeric ProteinsCommunitiesComplexConsumptionCoupledDataDevelopmentDiseaseDissectionEnvironmentFOXO1A geneFutureGenesGeneticGenetic TranscriptionGoalsIndividualJointsKnowledgeLeadMalignant Childhood NeoplasmMalignant NeoplasmsMentorshipMethodsMolecularMolecular TargetNatureOncogenicPAX3 genePhotoaffinity LabelsPrognosisProtacProteinsProteomeReportingResearchResistanceSeriesSiteStructureTertiary Protein StructureTestingTherapeuticTimeTrainingValidationbasedrug discoveryexperimental studyfollow-upgene translocationinhibitorinsightknock-downnovelnovel therapeuticsscreeningsmall moleculesmall molecule inhibitortargeted treatmenttherapeutic targettranscription factorubiquitin-protein ligase
项目摘要
PROJECT SUMMARY
Fusion transcription factors (TFs) are an enticing class of cancer targets. When present in a malignancy, these
chimeric proteins are often the primary oncogenic drivers, and genetic knockdown of the fusion TF often leads
to cell death or differentiation. However, fusion TFs are an exceptionally difficult class of proteins to target with
small molecule inhibitors. Chief among the challenges of targeting fusion TFs is the significant degree of intrinsic
disorder and the lack of mechanistic characterization of individual fusions, limiting the ability to execute structure
and/or function-driven approaches to developing inhibitors. Strategies that enable direct targeting of fusion TF
function without the need for extensive functional characterization of the fusion TF are therefore highly valuable.
In this proposal, I will develop generalizable and mechanistically unbiased approaches to discover inhibitors of
the fusion TF PAX3-FOXO1 using small molecule microarray (SMM) screening strategies. Via the training plan
detailed herein, I will acquire expertise in several chemical biology strategies that are critical to accomplishing
this important objective. The proposed research will be further facilitated by an exceptional training environment
that provides me with mentorship from scientific leaders in cancer biology and TF inhibitor development.
Preliminary data indicates that PAX3-FOXO1 is ligandable; a small proof-of-concept screen produced two
selective hit molecules, one of which was confirmed to directly bind PAX3-FOXO1 and inhibit its function in
follow-up assays. Building on this preliminary data, I hypothesize molecules that directly target PAX3-FOXO1 or
its binding partners can be identified via joint analysis of SMM screens against PAX3-FOXO1 in cell lysate and
purified protein formats. In Aim 1, I will identify functionally active direct binders of PAX3-FOXO1 and identify
binding sites for a series of the most potent molecules. Structural characterization of one of these sites and its
interactions with binders will provide critical insights about small molecule recognition that will serve as the basis
for future structure-based optimization efforts. In Aim 2, I will identify active molecules that bind to functionally
vulnerable PAX3-FOXO1 interaction partners. Detailed target identification efforts using photo-affinity labeling
approaches will identify the molecular target and binding site of a lead molecule, and target validation
experiments will characterize the function of the target protein in PAX3-FOXO1-driven transcription. In Aim 3, I
will develop a PAX3-FOXO1 proteolysis targeting chimaera (PROTAC) degrader by identifying high-affinity
PAX3-FOXO1 binders and subjecting them to an efficient screening and optimization strategy to identify the
combination of PAX3-FOXO1 binder, linker, and E3 ligase binder that leads to the most potent degradation. This
PAX3-FOXO1 PROTAC, representing the first targeted degrader of any fusion TF, will be extensively
characterized and made available to the research community as a chemical probe. The generalizable and
unbiased approaches outlined herein will enable novel insights about fusion TF vulnerabilities to be obtained
concurrently with the development of chemical probes that target these weaknesses.
项目摘要
融合转录因子(TF)是一类诱人的癌症靶点。当存在于恶性肿瘤中时,这些
嵌合蛋白通常是主要的致癌驱动因子,融合TF的基因敲低通常导致
细胞死亡或分化。然而,融合TF是一种非常难靶向的蛋白质
小分子抑制剂。靶向融合TF的主要挑战是显著程度的内在缺陷。
混乱和缺乏个别融合的机械表征,限制了执行结构的能力
和/或功能驱动的方法来开发抑制剂。能够直接靶向融合TF的策略
因此,不需要融合TF的广泛功能表征的功能是非常有价值的。
在这个建议中,我将开发可推广的和机械上无偏见的方法来发现抑制剂,
融合TF PAX 3-FOXO 1使用小分子微阵列(SMM)筛选策略。通过培训计划
在此详细介绍,我将获得几个化学生物学策略的专业知识,这些策略对实现
这一重要目标。一个特殊的培训环境将进一步促进拟议的研究
这为我提供了来自癌症生物学和TF抑制剂开发科学领导者的指导。
初步数据表明PAX 3-FOXO 1是可配体的;一个小的概念验证筛选产生了两个
选择性命中分子,其中之一被证实直接结合PAX 3-FOXO 1,并抑制其功能,
后续分析。基于这些初步数据,我假设直接靶向PAX 3-FOXO 1或
其结合配偶体可以通过对细胞裂解物中针对PAX 3-FOXO 1的SMM筛选的联合分析来鉴定,
纯化的蛋白质形式。在目标1中,我将鉴定PAX 3-FOXO 1的功能活性直接结合剂,并鉴定
一系列最有效分子的结合位点。这些位点之一的结构表征及其
与粘合剂的相互作用将提供关于小分子识别的关键见解,
未来的结构优化工作。在目标2中,我将识别与功能性结合的活性分子
易受攻击的PAX 3-FOXO 1相互作用伙伴。使用光亲和标记的详细目标识别工作
这些方法将确定先导分子的分子靶点和结合位点,
实验将表征靶蛋白在PAX 3-FOXO 1驱动的转录中的功能。在目标3中,我
将开发PAX 3-FOXO 1蛋白水解靶向嵌合体(PROTAC)降解剂,
PAX 3-FOXO 1结合剂,并使它们经受有效的筛选和优化策略以鉴定PAX 3-FOXO 1结合剂。
PAX 3-F0 X 01结合剂、接头和E3连接酶结合剂的组合,其导致最有效的降解。这
PAX 3-FOXO 1 PROTAC代表了任何融合TF的第一个靶向降解剂,将被广泛应用于
表征并作为化学探针提供给研究界。可推广的和
本文概述的无偏方法将使人们能够获得有关融合TF脆弱性的新见解
同时开发针对这些弱点的化学探针。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Drugging Fuzzy Complexes in Transcription.
- DOI:10.3389/fmolb.2021.795743
- 发表时间:2021
- 期刊:
- 影响因子:5
- 作者:Su BG;Henley MJ
- 通讯作者:Henley MJ
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Matthew James Henley其他文献
Matthew James Henley的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 1.17万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 1.17万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 1.17万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 1.17万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 1.17万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 1.17万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 1.17万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 1.17万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 1.17万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 1.17万 - 项目类别:
Studentship














{{item.name}}会员




