Ubiquitin-independent targeted protein degradation

项目摘要 靶向蛋白质降解是药物发现中令人兴奋的新策略。这些药物具有 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 失活，可能引发与抑制单个活性位点不同的反应;（3） 每一个药物分子都可以结合多个靶分子， 而不是占用驱动，潜在的降低剂量和（4）简单的粘合剂可以 转化为功能性化合物，这可能会解决被认为是“不可药用”的目标。 诱导靶点降解的药物的合理设计几乎完全集中在 单一过表达策略：将靶蛋白定位于泛素E3连接酶。的 泛素化的主要作用是将靶蛋白定位于蛋白酶体，并且实验 来自几个实验室的研究表明，蛋白酶体定位足以诱导 降解这些观察结果表明，靶向蛋白的泛素独立的策略 降解，其中靶识别配体与蛋白酶体结合配体连接 （Proteasome recruiter）.直接定位于蛋白酶体避免了E3连接酶的问题 本土化战略。蛋白酶体招募者也有可能成为组织， 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的α环 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.