Ubiquitin-independent targeted protein degradation

不依赖泛素的靶向蛋白质降解

• 批准号: 10797292
• 负责人: Lizbeth K. Hedstrom
• 金额: $ 11.7万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797292
• 关键词: Active Sites; Address; Dose; Drug Design; Event; Goals; Grant; Laboratories; Ligand Binding; Ligands; Link; Malignant Neoplasms; Methods; Pharmaceutical Preparations; Post-Translational Protein Processing; Proteasome Binding; Proteins; Role; Site-Directed Mutagenesis; Tissues; Ubiquitin; Ubiquitination; drug discovery; experimental study; multicatalytic endopeptidase complex; particle; protein degradation; rational design; response; small molecule; ubiquitin-protein ligase

Project Summary / Abstract Targeted protein degradation is an exciting new strategy in drug discovery. Such drugs have several potential advantages: (1) new protein targets must be synthesized to reverse the effect of the drug, potentially prolonging efficacy; (2) all the domains of the target protein are inactivated, potentially eliciting different responses than inhibition of a single active site; (3) each drug molecule can inactivate multiple target molecules, making efficacy event-driven rather than occupancy-driven, potentially lowering dose and (4) simple binders can be converted into functional compounds, which may address targets considered “undruggable”. The rational design of drugs inducing target degradation has almost exclusively focused on a single over-arching strategy: localization of the target protein to a ubiquitin E3 ligase. The primary role of ubiquitination is to localize the target protein to the proteasome, and experiments from several laboratories demonstrate that proteasome localization is sufficient to induce degradation. These observations suggest a ubiquitin-independent strategy for targeted protein degradation, wherein a target recognition ligand is linked to a proteasome binding ligand (proteasome recruiter). Direct localization to the proteasome avoids issues with E3 ligase localization strategies. Proteasome recruiters also have the potential to be tissue, compartment and cancer-specific. The goal of this transformative grant is to demonstrate the feasibility of proteasome recruiters using three strategies: (1) Localization to the 19S regulatory particle; (2) Localization to a proteasome shuttle factor and (3) localization to the alpha ring of the 20S proteasome.

项目概要/摘要 靶向蛋白质降解是药物发现中令人兴奋的新策略。 潜在优势：（1）必须合成新的蛋白质靶标才能逆转药物的作用， (2) 靶蛋白的所有结构域均失活，可能引发 (3) 每个药物分子可以灭活多个 目标分子，使功效由事件驱动而不是占用驱动，有可能降低剂量和 (4) 简单的粘合剂可以转化为功能化合物，这可以解决所考虑的目标 “不可成药”。诱导靶点降解的药物的合理设计几乎完全集中在“不可成药”上。 单一的总体策略：将靶蛋白定位到泛素 E3 连接酶的主要作用。 泛素化是将目标蛋白定位到蛋白酶体上，多个实验室的实验 证明蛋白酶体定位足以诱导降解。 靶向蛋白质降解的不依赖于泛素的策略，因此连接了目标识别配体 蛋白酶体结合配体（蛋白酶体招募剂）的直接定位可避免出现问题。 借助 E3 连接酶定位策略，蛋白酶体招募剂也有可能成为组织， 这项变革性拨款的目标是证明隔室和癌症特定的可行性。 蛋白酶体招募者使用三种策略：(1) 定位到 19S 调节颗粒；(2) 定位； 蛋白酶体穿梭因子和 (3) 定位于 20S 蛋白酶体的 α 环。