Developing Autophagy-Targeting Chimeras and Optimizing Cell Penetration of Large-Molecule Therapeutics
开发自噬靶向嵌合体并优化大分子治疗的细胞渗透
基本信息
- 批准号:10558145
- 负责人:
- 金额:$ 57.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-01 至 2028-02-29
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptedAlgorithm DesignAreaAutophagocytosisBindingBiological AssayCRISPR screenCellsCellular biologyChimera organismCytosolDNA DamageDataDegradation PathwayDiseaseEndosomesGeneticHumanKineticsLearningMalignant NeoplasmsMeasuresMediatingMethodsModelingMolecular EvolutionPenetrationProtacProtein FamilyProteinsSeriesStructureTestingTherapeuticTimeWorkcell typechemotherapydesigndrug developmentdrug discoveryinhibition of autophagyinhibitorinnovationnovelprotein degradationprotein protein interactionresearch and developmentscreeningsmall molecule inhibitorstapled peptide
项目摘要
The Kritzer lab focuses on inhibiting protein-protein interactions involved in autophagy. Autophagy is a protein
degradation pathway that is active in all human cells, and inhibiting autophagy shows promise as a therapy for
late-stage cancers especially in combination with DNA-damaging chemotherapies. Autophagy research and
drug development currently rely on compounds that inhibit autophagy indirectly. Better, more specific inhibitors
of autophagy would be broadly adopted. A large amount of genetics and cell biology work supports that
inhibiting the LC3/GABARAP family of proteins can block autophagy selectively. In one series of projects, we
will develop novel stapled peptide and small molecule inhibitors of LC3/GABARAP and evaluate them in
models of late-stage cancers and other diseases.
Because of our expertise in compounds that bind LC3/GABARAP proteins, we also propose to evaluate related
compounds as autophagy-targeting chimeras (AUTACs). These compounds could be used to selectively
degrade any proteins in the cell, similar to proteolysis-targeting chimeras (PROTACs) but potentially more
versatile and easier to develop. Based on strong preliminary data that validate the AUTAC concept, we will
develop novel AUTACs and demonstrate their ability to degrade endogenous proteins, unlocking a
broad new area for drug development in targeted protein degradation.
Over the course of developing stapled peptides as autophagy modulators, the Kritzer lab encountered a
common problem in the field: how to measure the amount that actually reaches the cytosol. In an
independent series of projects, the Kritzer lab has developed novel assays that quantitate the cytosolic
penetration of large-molecule therapeutics. In this proposal, we describe new opportunities to address
challenging problems in drug development for large-molecule therapeutics. We describe new methods to
measure penetration to different cellular compartments in any cell type, including primary cells. We also
describe a molecular evolution approach to develop a new “turn-on” assay that measures the real-time
kinetics of cytosolic penetration. We describe pooled CRISPR screens to reveal the cellular components
that mediate endosomal escape. Finally, we describe a novel screening platform that will allow us to screen
thousands to millions of molecules at a time for those that are most cell-penetrant; the new screen will be
incorporated into a design-test-learn cycle to produce data-driven design algorithms for cytosol-penetrant
molecules. All together, these data will represent a huge leap in our understanding of structure-penetration
relationships for several classes of large-molecule therapeutics.
Kritzer实验室专注于抑制参与自噬的蛋白质-蛋白质相互作用。自噬是一种蛋白质
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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Joshua A Kritzer其他文献
How to be quick on the uptake
如何快速理解
- DOI:
10.1038/nchembio.2183 - 发表时间:
2016-09-20 - 期刊:
- 影响因子:13.700
- 作者:
Joshua A Kritzer - 通讯作者:
Joshua A Kritzer
Magic bullets in nature's arsenal
大自然武库中的“魔弹”
- DOI:
10.1038/nchembio.407 - 发表时间:
2010-08-01 - 期刊:
- 影响因子:13.700
- 作者:
Joshua A Kritzer - 通讯作者:
Joshua A Kritzer
Joshua A Kritzer的其他文献
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{{ truncateString('Joshua A Kritzer', 18)}}的其他基金
High-Throughput Assays for Inhibitors of Understudied Bacterial Proteases
正在研究的细菌蛋白酶抑制剂的高通量测定
- 批准号:
9118235 - 财政年份:2015
- 资助金额:
$ 57.9万 - 项目类别:
High-Throughput Assays for Inhibitors of Understudied Bacterial Proteases
正在研究的细菌蛋白酶抑制剂的高通量测定
- 批准号:
9321116 - 财政年份:2015
- 资助金额:
$ 57.9万 - 项目类别:
High-Throughput Assays for Inhibitors of Understudied Bacterial Proteases
正在研究的细菌蛋白酶抑制剂的高通量测定
- 批准号:
8817739 - 财政年份:2015
- 资助金额:
$ 57.9万 - 项目类别:
Rapid Generation of Isoform-Selective Histone Deacetylase Inhibitors
快速生成异构体选择性组蛋白脱乙酰酶抑制剂
- 批准号:
8030563 - 财政年份:2011
- 资助金额:
$ 57.9万 - 项目类别:
Rapid Generation of Isoform-Selective Histone Deacetylase Inhibitors
快速生成异构体选择性组蛋白脱乙酰酶抑制剂
- 批准号:
8215725 - 财政年份:2011
- 资助金额:
$ 57.9万 - 项目类别:
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
- 批准号:
7981860 - 财政年份:2010
- 资助金额:
$ 57.9万 - 项目类别:
Mechanism of Amyloid Inhibition by Small Molecules
小分子抑制淀粉样蛋白的机制
- 批准号:
7113342 - 财政年份:2006
- 资助金额:
$ 57.9万 - 项目类别:
Mechanism of Amyloid Inhibition by Small Molecules
小分子抑制淀粉样蛋白的机制
- 批准号:
7474647 - 财政年份:2006
- 资助金额:
$ 57.9万 - 项目类别:
Mechanism of Amyloid Inhibition by Small Molecules
小分子抑制淀粉样蛋白的机制
- 批准号:
7454964 - 财政年份:2006
- 资助金额:
$ 57.9万 - 项目类别:
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