Ubiquitin-independent targeted protein degradation

项目摘要 靶向蛋白质降解是药物发现中一种令人兴奋的新策略。这类药物有 几个潜在的优势：(1)必须合成新的蛋白质靶点来逆转这种效应 (2)靶蛋白的所有结构域都是 灭活的，可能引起与抑制单个活性部位不同的反应；(3) 每个药物分子可以灭活多个靶分子，使疗效受到事件驱动 而不是占用驱动的，潜在地降低剂量和(4)简单的粘结剂可以 转化为功能性化合物，可能针对被认为“无法下药”的靶标。 诱导靶向降解的药物的合理设计几乎完全集中在一种 单一总体策略：将目标蛋白定位于泛素E3连接酶。这个 泛素化的主要作用是将目标蛋白定位到蛋白酶体，并进行实验 来自几个实验室的研究表明，蛋白酶体定位足以诱导 退化。这些观察结果提示了一种靶向蛋白的泛素非依赖性策略。 降解，其中靶识别配体连接到蛋白酶体结合配体 (蛋白酶体招聘人员)。直接定位到蛋白酶体避免了E3连接酶的问题 本地化战略。蛋白酶体招募者也有可能是组织、隔间 而且是癌症特异性的。这一变革性赠款的目标是证明 蛋白酶体招募者使用三种策略：(1)定位到19s调控颗粒；(2) 蛋白酶体穿梭因子的定位和(3)20年代阿尔法环的定位 蛋白酶体。

Project Summary 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.