The molecular basis of IMiD induced neo-substrate recruitment to the CRL4CRBN ubiquitin E3 ligase

IMiD 诱导 CRL4CRBN 泛素 E3 连接酶招募新底物的分子基础

基本信息

批准号：
10627797
负责人：
Eric Sebastian Fischer
金额：
$ 38.88万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627797
关键词：
8p11 Acute Address Affect Alleles Binding Biological Biological Models Birth C2H2 Zinc Finger Cells Characteristics Chemicals Chemistry Child Chimeric Proteins Clinic Clinical Complex Congenital Abnormality Data Development Dysmyelopoietic Syndromes Embryo Engineering Eukaryota Explosion FDA approved FGFR1 gene Family Future Glues Goals Grant Hematologic Neoplasms Human Human Genetics Knock-in Lead Learning Ligase Malignant Neoplasms Marketing Mass Spectrum Analysis Measurement Mediating Memory Missense Mutation Modality Molecular Morning Sickness Multiple Myeloma Mus Mutation Myeloproliferative disease Oncogenes Oncogenic Pharmaceutical Preparations Pharmacotherapy Phenocopy Phocomelia Physiological Play Pregnancy Pregnant Women Proteins Proteomics RBX1 gene Recording of previous events Research Resources Role Self Mutilation Structure Syndrome Technology Teratogenic effects Teratogens Testing Thalidomide Therapeutic Therapeutic Effect Time Toxicity Tests Type 1 Duane Retraction Syndrome Withdrawal Work Zinc Fingers analog cancer therapy casein kinase I chromosome 5q loss clinical development consanguineous family effective therapy gain of function human embryonic stem cell immune modulating agents in vivo in vivo Model inhibitor insight lenalidomide loss of function member mouse model neurodevelopment new therapeutic target novel novel therapeutics phosphoric diester hydrolase pomalidomide preclinical development prevent protein degradation rational design recruit response scaffold severe intellectual disability small molecule therapeutics standard of care targeted treatment tool transcription factor ubiquitin ligase ubiquitin-protein ligase

项目摘要

Project Summary Developed in the 1950s, Thalidomide was used to treat morning sickness in the early stages of pregnancy, which led to the birth of thousands of children with severe birth defects and subsequent withdrawal from the market. Today, thalidomide and its analogs lenalidomide and pomalidomide (collectively known as IMiDs) are FDA approved drugs and effective treatments for hematologic malignancies such as multiple myeloma and Del(5q) MDS. But despite over 60 years of research, the mechanistic understanding of how these molecules cause the characteristic birth defects is only just beginning to unravel. Due to the wide use of IMiDs in the clinic, and the recent explosion in the development of targeted protein degradation therapies based often on the original thalidomide scaffold, it is more critical than ever that we understand the full range of potential activities that IMiDs provoke. Here, we propose to explore the broad range of potential activities that result from these IMiD-like molecules binding to the E3 ligase CUL4-RBX1-DDB1-CRBN (CRL4CRBN) and redirecting its activity towards different targets. Specifically, in aim 1, we will engineer an in vivo mouse model of Sall4 degradation to dissect how thalidomide-mediated degradation of Sall4 leads to teratogenicity. We will do this through a combination of expression analyses and developmental measurements to assess the affect that IMiD molecules have on the developing embryo. This will not only enable the study of the mechanism of teratogenic activity of these drugs but will also provide a critical model system for testing the toxicity of current and future versions of these molecules. Not only do these molecules induce a gain-of-function to target new proteins, but they also induce a loss-of-function and in aim 2, we propose to use novel mass spectrometry-based proteomics technology in combination with potent and selective tool compounds to explore the biological consequences of blocking CRBN activity. We have previously shown that we can expand the scope of IMiD targets through rational design of new IMiD-like molecules capable of degrading new proteins related to known targets. In aim 3, we propose to expand the target scope even further by developing novel chemistry to target structurally diverse proteins that have a strong therapeutic rationale, thus providing proof-of-concept for target expansion and providing chemical leads for new therapeutic targets. The overarching goal of this grant is to explore the full range of potential activities of the widely utilized CRL4CRBN ligase by identifying and exploring the mechanistic consequences of degrading its physiological and IMiD-induced targets, as well as seeking to expand its target space into currently undruggable territories.

项目摘要在1950年代开发的沙利度胺被用来治疗怀孕初期的孕吐，导致数千名患有严重出生缺陷的儿童的诞生，随后退出市场。如今，沙利度胺及其类似物列纳莱度胺和pomalidomide（统称为Imids）是FDA 批准的药物和有效治疗血液系统恶性肿瘤，例如多发性骨髓瘤和DEL（5q） MDS。但是尽管进行了60多年的研究，但对这些分子如何引起的机械理解特征性的先天缺陷才刚刚开始瓦解。由于在诊所中广泛使用IMID，以及靶向蛋白质降解疗法的开发中的最新爆炸经常基于原始沙利度胺脚手架，比以往任何时候惹。在这里，我们建议探索这些类似IMID的广泛潜在活动与E3连接酶Cul4-RBX1-DDB1-CRBN（CRL4CRBN）结合的分子，并将其活性重定向不同的目标。具体而言，在AIM 1中，我们将设计一个体内鼠标sall4降解模型以剖析沙利度胺介导的SALL4的降解如何导致致畸性。我们将通过结合表达分析和发育测量值，以评估IMID分子对开发胚胎。这不仅可以研究这些药物的致病活性机制但还将提供一个关键的模型系统，用于测试当前和未来版本的毒性分子。这些分子不仅会引起功能获得的靶向新蛋白质，而且还诱导功能丧失，在AIM 2中，我们建议在基于质谱的新型蛋白质组学技术中使用新颖的蛋白质组学技术结合有效和选择性的工具化合物，以探索阻断CRBN的生物学后果活动。我们以前已经表明，我们可以通过合理的新设计扩大IMID目标的范围 IMID样分子能够降解与已知靶标相关的新蛋白质。在AIM 3中，我们建议扩展目标范围甚至通过开发新的化学反应来进一步靶向具有结构上多样化的蛋白质强大的治疗原理，因此为目标扩展提供了概念验证并提供化学铅用于新的治疗靶标。这笔赠款的总体目标是探索通过识别和探索降解的机械后果，广泛使用的CRL4CRBN连接酶生理和IMID诱导的目标，并试图将其目标空间扩展到当前不足领土。