Ubiquitin-independent targeted protein degradation

项目总结/摘要 靶向蛋白质降解是药物发现中令人兴奋的新策略。这些药物有几种 潜在的优点：（1）必须合成新的蛋白质靶以逆转药物的作用， 潜在地延长功效;（2）靶蛋白的所有结构域都被灭活，潜在地引发 与抑制单个活性位点不同的反应;（3）每个药物分子可以抑制多个 靶向分子，使疗效事件驱动而不是占用驱动，可能降低剂量， (4)简单的粘合剂可以转化为功能性化合物，其可以针对所考虑的目标， “无法抗拒”诱导靶点降解的药物的合理设计几乎完全集中在 一个单一的过度修饰策略：将靶蛋白定位于泛素E3连接酶。的主要作用 泛素化是将靶蛋白定位于蛋白酶体，几个实验室的实验 证明蛋白酶体定位足以诱导降解。这些观察表明， 用于靶向蛋白质降解的不依赖于泛素的策略，其中靶识别配体被连接 蛋白酶体结合配体（蛋白酶体募集剂）。直接定位于蛋白酶体避免了问题 用E3连接酶定位策略。蛋白酶体也有可能是组织， 隔室和癌症特异性。这项变革性赠款的目标是证明以下方面的可行性： 蛋白酶体募集者使用三种策略：（1）定位于19 S调节颗粒;（2）定位于 蛋白酶体穿梭因子和（3）定位于20 S蛋白酶体的α环。

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.