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：
10374974
负责人：
Eric Sebastian Fischer
金额：
$ 40.66万
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/10374974
关键词：
8p11 Acute Address Affect Alleles Behavior Binding Biological Biological Models Birth C2H2 Zinc Finger CSNK1A1 gene 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 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 base cancer therapy casein kinase I chromosome 5q loss clinical development consanguineous family effective therapy gain of function human embryonic stem cell 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 pre-clinical 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.

项目概要沙利度胺于 20 世纪 50 年代开发，用于治疗妊娠早期的孕吐，导致数千名患有严重先天缺陷的儿童出生并随后退出市场。如今，沙利度胺及其类似物来那度胺和泊马度胺（统称为 IMiD）已获得 FDA 批准针对血液系统恶性肿瘤（如多发性骨髓瘤和 Del(5q)）的批准药物和有效治疗方法 MDS。但尽管经过 60 多年的研究，对这些分子如何导致特征性出生缺陷才刚刚开始显现。由于IMiD在临床上的广泛使用，以及最近，基于原始蛋白降解疗法的靶向蛋白降解疗法的发展呈爆炸式增长。沙利度胺支架，我们比以往任何时候都更重要的是，我们了解 IMiD 的全部潜在活性惹。在这里，我们建议探索这些类似 IMiD 的广泛潜在活动分子与 E3 连接酶 CUL4-RBX1-DDB1-CRBN (CRL4CRBN) 结合并将其活性重定向至不同的目标。具体来说，在目标 1 中，我们将设计一个 Sall4 降解的体内小鼠模型来剖析沙利度胺介导的 Sall4 降解如何导致致畸性。我们将通过组合来做到这一点表达分析和发育测量，以评估 IMiD 分子对发育中的胚胎。这不仅使研究这些药物的致畸活性机制成为可能但还将提供一个关键的模型系统来测试当前和未来版本的毒性分子。这些分子不仅诱导靶向新蛋白质的功能获得，而且还诱导功能丧失，在目标 2 中，我们建议使用基于质谱的新型蛋白质组学技术与有效且选择性的工具化合物相结合，探索阻断 CRBN 的生物学后果活动。我们之前已经表明，我们可以通过合理设计新的方法来扩大 IMiD 目标的范围。 IMiD 类分子能够降解与已知靶标相关的新蛋白质。在目标 3 中，我们建议扩大通过开发新颖的化学方法来靶向具有不同结构的蛋白质，从而进一步扩大目标范围强有力的治疗原理，从而为靶点扩展提供概念验证并提供化学先导化合物寻找新的治疗靶点。这笔赠款的总体目标是探索全方位的潜在活动通过识别和探索广泛使用的 CRL4CRBN 连接酶降解的机制后果生理和 IMiD 诱导的目标，以及寻求将其目标空间扩展到目前不可成药的区域领土。