Discovery of small molecules inhibiting Toll-like receptor-mediated inflammation
发现抑制 Toll 样受体介导炎症的小分子
基本信息
- 批准号:10060723
- 负责人:
- 金额:$ 51.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-06-14 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:Adaptor Signaling ProteinAgonistAlgorithmsAutoimmune DiseasesBindingBiochemicalBiological AssayBiologyCell LineCellsChemicalsChemistryClinical PathwaysCollectionComplexDataDisadvantagedDiseaseDoseDrug ScreeningDrug TargetingEnvironmentEstrogen Receptor alphaEtiologyEventFamilyFamily memberFutureGoalsIRAK1 geneImmuneImmune responseInflammationInflammatoryLibrariesMalignant NeoplasmsMass Spectrum AnalysisMediatingMedicalMethodsMolecularPathologicPathway interactionsPatientsPharmaceutical ChemistryPharmaceutical PreparationsPhenotypePhysiologicalProcessProdrugsProteinsProteomicsPyrazolesReceptor ActivationReceptor InhibitionReceptor SignalingReporterResearch PersonnelSaint Jude Children&aposs Research HospitalScreening procedureSepsisSeriesSignal PathwaySignal TransductionSignaling ProteinSpecificityStimulusStreamSystemTIRAP geneTLR2 geneTLR7 geneTRAF6 geneTestingTimeTissuesToll-Like Receptor PathwayToll-like receptorsTreesanalogbasedesigndrug developmenthigh throughput screeninginhibitor/antagonistmacrophagemembermethod developmentnew therapeutic targetnovelnovel strategiesnovel therapeuticspathogenpreventrecruitresponsescreeningsmall moleculesmall molecule inhibitortoolubiquitin ligase
项目摘要
ABSTRACT
Members of the Toll-like receptor (TLR) family recognize various pathogen- and host tissue-derived
molecules, and initiate immune responses physiologically via inflammatory processes. Exaggerated or
prolonged TLR activation, however, leads to pathological inflammation as observed in a large number of
etiologically diverse diseases, such as bacterial sepsis, autoimmune diseases and cancer. Despite the
apparent need, no effective small molecule inhibitors of the canonical TLR signaling pathway are available,
neither as probes to explore TLR biology nor as drugs to treat patients. The goal of this project is to identify
small molecule inhibitors of TLR-specific signaling pathways. One factor impeding drug development is the
signaling mechanism involved, i.e. a series of protein interactions that are inherently difficult for targeted drug
development. Specifically, TLRs signal via the hierarchically acting proteins TIRAP, MyD88, IRAKs and
TRAF6, the latter defining the border towards common, TLR-non-specific pathways. Thus, signaling events up-
stream of TRAF6 represent the desirable ‘drug target window’. We have developed a unique, cellular high
throughput screening (HTS) platform that retains the advantages of phenotypic screening, i.e. the testing of
complex responses in the natural environment of cells but, at the same time, mitigates the major disadvantage
by eliminating non-specific compounds. Key feature of this system are drug-inducible (GyrB-fused) forms of
TIRAP, MyD88 and TRAF6, whose responses reflect the ‘signaling level’ of compound activity. We have
validated this approach using the St. Jude bioactive compound library, which allowed in consecutive screening
steps facile elimination of non-specific hits (>99% of hits blocking TRAF6), and identification of one compound
as selective TLR inhibitor. Using this compound as tool molecule, we established a hit advancement algorithm
including SAR analysis, quantitative proteomics, protein interaction- and cellular thermal shift assays (CETSA),
collectively validating this approach as discovery tool for TLR antagonists. Here we propose to perform a HTS
of the St. Jude collection (~650,000 compounds) to identify a set of TLR inhibitory compounds with defined
chemotype. The primary screen (single concentration) based on TIRAP-GyrB identifies compounds that act at
any possible level of the TLR pathway. The secondary screen (dose-response) based on TIRAP-, MyD88-
and TRAF6-GyrB cells defines the signaling level. Compounds inhibiting TRAF6 will be discarded as TLR-non-
specific. Inhibition of TIRAP or MyD88 will define TLR-specific compounds. TLR-specific compounds will be
validated by physiological TLR stimulation and prioritized based on chemoinformatics analysis and
chemistry inspection. SAR analysis will be conducted to validate chemotype tractability based on
available analogs and exploratory chemistry, and mentioned biochemical algorithm will be used to define
mechanism of action and drug target. In summary, we expect to identify diverse chemotypes with defined,
chemically tractable TLR-inhibitory activity as starting point for successful, future drug development.
摘要
Toll样受体(TLR)家族的成员识别各种病原体和宿主组织来源
分子,并通过炎症过程从生理上启动免疫反应。夸张或夸张
然而,TLR激活时间延长会导致病理性炎症,观察到在许多
病因多样的疾病,如细菌败血症、自身免疫性疾病和癌症。尽管
显然需要,规范的TLR信号通路没有有效的小分子抑制剂,
既不作为探索TLR生物学的探针,也不作为治疗患者的药物。该项目的目标是确定
TLR特异性信号通路的小分子抑制物。阻碍药物开发的一个因素是
涉及的信号机制,即一系列靶向药物本身难以实现的蛋白质相互作用
发展。具体地说,TLRs通过分级作用的蛋白质TIRAP、MyD88、IRAKs和
TRAF6,后者定义了通向共同的、TLR-非特定路径的边界。因此,向事件发送信号-
TRAF6代表理想的“药物靶向窗口”。我们已经开发出一种独特的,细胞的快感
吞吐量筛选(HTS)平台,保留表型筛选的优势,即测试
细胞在自然环境中的复杂反应,但同时也缓解了主要的缺点
通过消除非特定化合物。该系统的主要特征是药物诱导(gyrB融合)形式的
TIRAP、MyD88和TRAF6,它们的反应反映了化合物活性的信号水平。我们有
使用St.Jude生物活性化合物文库验证了这种方法,该文库允许在连续筛选中
轻松消除非特定命中(>;99%的命中阻止TRAF6),并识别一种化合物
作为选择性TLR抑制剂。以该化合物为工具分子,建立了HIT推进算法
包括SAR分析、定量蛋白质组学、蛋白质相互作用和细胞热位移分析(CETSA),
共同验证了该方法作为TLR拮抗剂的发现工具。在这里,我们建议执行HTS
对St.Jude集合(~650,000种化合物)进行鉴定,以鉴定一组具有定义的TLR抑制化合物
化学型。基于TIRAP-GyrB的初级筛选(单一浓度)识别作用于
TLR通路的任何可能水平。基于TIRAP-,MyD88-的二次筛选(剂量-反应)
而TRAF6-GyrB细胞定义了信号水平。抑制TRAF6的化合物将作为TLR-Non-丢弃
具体的。抑制TIRAP或MyD88将定义TLR特异性化合物。TLR特定的化合物将是
通过生理TLR刺激进行验证,并基于化学信息学分析和
化学检验。将进行sar分析,以验证化学类型的可操作性,基于
可用的类似物和探索性化学,以及所提到的生物化学算法将用于定义
作用机制和药物靶点。总而言之,我们希望用定义的、
化学上易于处理的TLR抑制活性,作为成功的未来药物开发的起点。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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HANS HAECKER其他文献
HANS HAECKER的其他文献
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{{ truncateString('HANS HAECKER', 18)}}的其他基金
A phospho-tyrosine-based signaling module controlling TLR-mediated inflammatory disease.
一种基于磷酸酪氨酸的信号传导模块,控制 TLR 介导的炎症性疾病。
- 批准号:
10661819 - 财政年份:2022
- 资助金额:
$ 51.53万 - 项目类别:
A phospho-tyrosine-based signaling module controlling TLR-mediated inflammatory disease.
一种基于磷酸酪氨酸的信号传导模块,控制 TLR 介导的炎症性疾病。
- 批准号:
10504686 - 财政年份:2022
- 资助金额:
$ 51.53万 - 项目类别:
Pathogenic role of innate immune cells in lupus nephritis
先天免疫细胞在狼疮性肾炎中的致病作用
- 批准号:
10385854 - 财政年份:2019
- 资助金额:
$ 51.53万 - 项目类别:
Pathogenic role of innate immune cells in lupus nephritis
先天免疫细胞在狼疮性肾炎中的致病作用
- 批准号:
10132979 - 财政年份:2019
- 资助金额:
$ 51.53万 - 项目类别:
Pathogenic role of innate immune cells in lupus nephritis
先天免疫细胞在狼疮性肾炎中的致病作用
- 批准号:
9925183 - 财政年份:2019
- 资助金额:
$ 51.53万 - 项目类别:
Pathogenic role of innate immune cells in lupus nephritis
先天免疫细胞在狼疮性肾炎中的致病作用
- 批准号:
10601014 - 财政年份:2019
- 资助金额:
$ 51.53万 - 项目类别:
Discovery of small molecules inhibiting Toll-like receptor-mediated inflammation
发现抑制 Toll 样受体介导炎症的小分子
- 批准号:
10201505 - 财政年份:2018
- 资助金额:
$ 51.53万 - 项目类别:
TLR-mediated Signaling Complex Formation and Regulation of Effector Functions
TLR 介导的信号复合物的形成和效应器功能的调节
- 批准号:
7696936 - 财政年份:2009
- 资助金额:
$ 51.53万 - 项目类别:
TLR-mediated Signaling Complex Formation and Regulation of Effector Functions
TLR 介导的信号复合物的形成和效应器功能的调节
- 批准号:
8289414 - 财政年份:2009
- 资助金额:
$ 51.53万 - 项目类别:
TLR-mediated Signaling Complex Formation and Regulation of Effector Functions
TLR 介导的信号复合物的形成和效应器功能的调节
- 批准号:
8091297 - 财政年份:2009
- 资助金额:
$ 51.53万 - 项目类别:
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