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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：
9355586
负责人：
Daniel Bondeson
金额：
$ 4.4万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-21 至 2018-09-13
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9355586
关键词：
Advanced Development Animal Model Binding Biochemical Biochemical Pathway Biodistribution Biological Assay Biology Cancer Biology Cell Culture Techniques Cell Proliferation Cells Chemicals Chimera organism Complex Data Set Development Disease Dose Down-Regulation Failure Fluorescence Polarization Generations Goals Human Immune In Vitro Laboratories Libraries Ligand Binding Ligands MAP Kinase Gene Malignant Neoplasms Mediating Mentors Modeling Names Nature Pathway interactions Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Phenotype Phosphotransferases Proteins Proteolysis Proteome Quality Control RNA Interference Reaction Recruitment Activity Research Research Project Grants Role Signal Pathway System Techniques Technology Therapeutic Thinking Training Ubiquitination Work base biological systems biophysical properties design experience genetic manipulation high throughput screening in vivo insight interest kinase inhibitor knock-down mouse model next generation novel oncology response scaffold screening small molecule small molecule inhibitor stoichiometry success tissue culture tool tool development treatment effect ubiquitin-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.

项目概要我的博士研究经验集中在使用化学工具来纠正扰动生物系统，主要是癌症。克鲁斯实验室最近开发的工具，蛋白水解靶向嵌合体（PROTAC），可以降解感兴趣的蛋白质，而无需任何基因操纵。到目前为止，我一直致力于将 PROTAC 作为一种有价值的工具。我已经表明这些化合物的行为符合我们提出的机制，即它们特异性且有效地降解感兴趣的蛋白质，并且 PROTAC 可以降解其动物模型中的目标。对于 F99 阶段，我将专注于开发选择性配体可在 PROTAC 中用于降解假激酶 KSR。该蛋白质没有突变或在癌症中被激活，但会上调许多不同癌症中涉及的 Ras-MAPK 通路。通过将高通量筛选与药物化学相结合，我将首先开发来自已知激酶抑制剂库的选择性配体。一旦配体被开发出来， PROTAC 将基于该配体合成，并评估细胞中 KSR 的降解情况。我然后将使用该工具进一步阐明 KSR 在 Ras-MAPK 中的脚手架作用通过使用高含量肽阵列来分析信号通路和其他细胞信号通路。这个项目是将化学生物学工具与癌症“系统级”见解相结合的一个例子。在我的 K00阶段，我希望通过接受高内容剖析培训来延续这个思路用于研究经常被改变和错误调节的复杂生化环境的技术癌症并确定新的目标。通过将综合“组学”技术与化学相结合生物学，我将致力于为新目标开发新的化学工具。