Investigating degradation as a therapeutic strategy against the Pseudo-kinase KSR
研究降解作为针对假激酶 KSR 的治疗策略
基本信息
- 批准号:10232084
- 负责人:
- 金额:$ 10.1万
- 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:2018-09-14 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:Advanced DevelopmentAnimal ModelBindingBiochemicalBiochemical PathwayBiodistributionBiological AssayBiologyCancer BiologyCell Culture TechniquesCell ProliferationCellsChemicalsComplexDevelopmentDiseaseDoseDown-RegulationFailureFluorescence PolarizationGenerationsGoalsHumanImmuneIn VitroLaboratoriesLibrariesLigand BindingLigandsMAP Kinase GeneMalignant NeoplasmsMediatingMentorsModelingNamesNatureOncologyPathway interactionsPeptidesPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPhasePhenotypePhosphotransferasesProtacProteinsProteomeQuality ControlRNA InterferenceReactionResearchResearch Project GrantsRoleSignal PathwaySystemTechniquesTechnologyTherapeuticThinkingTrainingUbiquitinationWorkbasebiological systemsbiophysical propertiesdesignexperiencegenetic manipulationhigh throughput screeningin vivoinsightinterestkinase inhibitorknock-downlarge datasetsmouse modelnext generationnovelrecruitresponsescaffoldscreeningsmall moleculesmall molecule inhibitorstoichiometrysuccesstissue culturetooltool developmenttreatment effectubiquitin-protein ligase
项目摘要
PROJECT SUMMARY
My doctoral research experience has focused on using chemical tools to correct perturbed
biological systems, primarily cancer. A recently develop tool in the Crews’ lab, proteolysis
targeting chimera (PROTACs), allows for the degradation of a protein of interest without any
genetic manipulation. Thus far, I have focused on establishing PROTACs as a valuable tool. I
have shown that these compounds behave according to our proposed mechanism, that they
specifically and potently degrade the protein of interest, and that PROTACs can degrade their
targets in animal models. For my F99 phase, I will focus on developing selective ligands that
can be used in a PROTAC to degrade the pseudo-kinase KSR. This protein is not mutated or
activated in cancer, but upregulates the Ras-MAPK pathway involved in many different cancers.
By combining high-throughput screening with medicinal chemistry, I will first develop the
selective ligand from a library of known kinase inhibitors. Once a ligand is developed, a
PROTAC will be synthesized based on that ligand and assessed for KSR-degradation in cells. I
will then use this tool to further clarify the scaffolding roles of KSR in the Ras-MAPK
pathway and other cellular signaling pathways by using high-content peptide arrays. This project
is an example of combining chemical biology tools with ‘systems-level’ insights in cancer. In my
K00 phase, I hope to continue this line of thinking by being trained in high-content profiling
techniques used to study the complex biochemical milieu that is often altered and mis-regulated
in cancer and identify new targets. By combining integrative ‘-omics’ techniques with chemical
biology, I will work to develop novel chemical tools for novel targets.
项目总结
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Systematic profiling of conditional degron tag technologies for target validation studies.
- DOI:10.1038/s41467-022-33246-4
- 发表时间:2022-09-20
- 期刊:
- 影响因子:16.6
- 作者:
- 通讯作者:
An In Vitro Pull-down Assay of the E3 Ligase:PROTAC:Substrate Ternary Complex to Identify Effective PROTACs.
E3 连接酶:PROTAC:底物三元复合物的体外下拉测定可识别有效的 PROTAC。
- DOI:10.1007/978-1-0716-1665-9_7
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Bondeson,DanielP;Smith,BlakeE;Buhimschi,AlexandruD
- 通讯作者:Buhimschi,AlexandruD
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Daniel Bondeson的其他文献
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{{ truncateString('Daniel Bondeson', 18)}}的其他基金
Investigating degradation as a therapeutic strategy against the Pseudo-kinase KSR
研究降解作为针对假激酶 KSR 的治疗策略
- 批准号:
10005892 - 财政年份:2018
- 资助金额:
$ 10.1万 - 项目类别:
Investigating degradation as a therapeutic strategy against the Pseudo-kinase KSR
研究降解作为针对假激酶 KSR 的治疗策略
- 批准号:
9355586 - 财政年份:2016
- 资助金额:
$ 10.1万 - 项目类别:
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