Degrader probes for necroptosis pathway

坏死性凋亡途径的降解探针

基本信息

批准号：
10408181
负责人：
Gregory D Cuny
金额：
$ 19.74万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-20 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408181
关键词：
Address Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Apoptosis Autoimmune BIRC4 gene Binding Biological Assay Biology COVID-19 Cell Death Cell Death Process Cells Cervix carcinoma Clinical Combined Modality Therapy Consequentialism Data Development Disease Event Family Family member Future Genetic Models Hela Cells Immunologics In Vitro Induction of Apoptosis Inflammatory Laboratories Ligands Link Mediating Molecular Molecular Probes Myeloid Cells NF-kappa B Necrosis Nerve Degeneration Pathologic Pathway interactions Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Phosphotransferases Physiology Play Process Property Protac Protein Family Protein Kinase Proteins Psoriasis Publishing RIPK1 gene RIPK3 gene Reagent Regulation Research Resistance Role Safety Series Signal Transduction Therapeutic Toxic effect Work autocrine base cancer cell cell killing design gain of function human disease improved in vivo inhibitor inhibitor-of-apoptosis protein innovation kinase inhibitor new therapeutic target novel strategies novel therapeutics overexpression pomalidomide protein degradation protein function refractory cancer scaffold small molecule ubiquitin-protein ligase

Address Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Apoptosis Autoimmune BIRC4 gene Binding Biological Assay Biology COVID-19 Cell Death Cell Death Process Cells Cervix carcinoma Clinical Combined Modality Therapy Consequentialism Data Development Disease Event Family Family member Future Genetic Models Hela Cells Immunologics In Vitro Induction of Apoptosis Inflammatory Laboratories Ligands Link Mediating Molecular Molecular Probes Myeloid Cells NF-kappa B Necrosis Nerve Degeneration Pathologic Pathway interactions Peripheral Pharmaceutical Chemistry Pharmaceutical Preparations Phenotype Phosphotransferases Physiology Play Process Property Protac Protein Family Protein Kinase Proteins Psoriasis Publishing RIPK1 gene RIPK3 gene Reagent Regulation Research Resistance Role Safety Series Signal Transduction Therapeutic Toxic effect Work autocrine base cancer cell cell killing design gain of function human disease improved in vivo inhibitor inhibitor-of-apoptosis protein innovation kinase inhibitor new therapeutic target novel strategies novel therapeutics overexpression pomalidomide protein degradation protein function refractory cancer scaffold small molecule ubiquitin-protein ligase

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项目摘要

ABSTRACT Receptor-interacting Protein Kinases 1 and 3 (RIPK1 and RIPK3) along with Mixed Lineage Kinase Domain- like (MLKL) pseudokinase are well-established players in a regulated necrotic cell death process, known as necroptosis. Activity of these proteins has been implicated in many disease states, including immunologic and inflammatory conditions. However, RIPK1 and RIPK3 scaffold functions that are distinct from their catalytic activities are much less explored. In addition, “kinase-domain” binding MLKL ligands developed thus far lacked uniform functional activities, suggesting need for a new strategy targeting this critical executioner of necroptosis. Consequently, molecular probes capable of selective degradation of these proteins will enable further progress in understanding necroptosis by elucidation of scaffold functions for these proteins. This work will also provide guidance for new therapeutic paradigms. To assess this hypothesis, proteolysis targeting chimeras (PROTACs) of RIPK3 and MLKL (Aim 1) will be generated leveraging previously identified ligands. These probes will be assessed for their ability to induce cellular degradation of RIPK3 and MLKL and, consequentially, to provide protection against pathologic necroptosis. Independently, probes that induce co- degradation of RIPK1 and Inhibitor of Apoptosis Proteins (IAPs) (Aim 2) will be developed, based on identification of new starting points for such molecules in our preliminary data. These co-degrader molecules will provide new options for inducing cell death in necroptosis-resistant cancer and activated myeloid cells. Overall, this project will provide critical data revealing the feasibility of targeting RIPK1, RIPK3 kinases and the pseudokinase MLKL for degradation as a new approach to understanding their kinase-independent functions that can also be leveraged in innovative therapeutic directions.

抽象的受体相互作用蛋白激酶1和3（RIPK1和RIPK3）以及混合谱系激酶结构域 - 像（MLKL）假子酶是受监管的坏死细胞死亡过程中成熟的参与者，称为坏死性。这些蛋白质的活性已在许多疾病状态中隐含，包括免疫学和炎症条件。但是，RIPK1和RIPK3脚手架功能与其催化不同活动的探索程度要少得多。此外，迄今为止缺乏“激酶域”结合MLKL配体统一的功能活动，表明需要针对这个关键执行者的新策略坏死性。因此，能够选择性降解这些蛋白质的分子问题将使通过阐明这些蛋白质的支架功能来理解坏死性的进一步进展。这项工作还将为新的治疗范式提供指导。为了评估这一假设，蛋白水解靶向 RIPK3和MLKL（AIM 1）的嵌合体（Protacs）将产生先前鉴定的配体的利用。这些问题将因其诱导RIPK3和MLKL的细胞降解的能力而评估，以及因此，为防止病理坏死性提供保护。独立地，影响共同的问题 RIPK1和凋亡蛋白抑制剂的降解（IAP）（AIM 2）将基于在我们的初步数据中鉴定此类分子的新起点。这些共脱生分子将为抗坏死性癌症和激活的髓样细胞的诱导细胞死亡提供新的选择。总体而言，该项目将提供关键数据，以揭示靶向RIPK1，RIPK3激酶和假子酶MLKL用于降解，这是一种理解其与激酶无关的功能的新方法这也可以用创新的治疗方向利用。