Development of a generalizable chemo-proteomics screening platform for small molecule degraders applied to HDACs

项目摘要 利用小分子降解剂靶向降解蛋白质是一种新兴的癌症治疗方法 治疗。与制造降解剂的传统抑制剂药物相比，降解剂有几个优点 有吸引力的新治疗实体。首先，降解剂可以在比抑制剂低得多的浓度下工作，因此 使用剂量较低，药物毒性较低。第二，降解者去除目标蛋白质 而不是简单地抑制蛋白质的酶活性，从而消除非酶 目的蛋白的活性。这种非酶活性在组蛋白脱乙酰基酶中尤其常见。 (HDAC)。第三，降解剂可以被用来瞄准通过传统手段被认为“无法下药”的目标， 它们代表了人类蛋白质组的80%，只要有蛋白质结合配体就行。然而， 目前开发降解剂的战略遵循的是一条相当经验性的路线，结果很偶然。在这里，我们建议 开发一种新的筛选平台来发现和开发降解剂分子。该战略涉及到 基于以蛋白质家族为靶点的混杂抑制剂的结构导向降解物文库设计 化学蛋白质组学筛选可降解蛋白家族成员和选择性降解物 他们。来自蛋白质组学筛选的大量数据使我们能够理解 降解物的化学结构和目标蛋白的降解力，这将反馈到下一轮 迭代文库的设计和筛选。这种通过蛋白质组学评估进行优化的迭代循环 事实证明，这是一种更有效的方法来产生选择性和有效的降解剂，用于开发治疗 生物学研究的候选者和化学探针者。我们将这一策略应用于一个重要的酶家族， HDAC，其特定的抑制剂很少可用。HDAC是许多不同种类的治疗靶点。 癌症和人类疾病。我们建议为一些HDAC成员开发选择性降解剂。 特别是，我们希望开发HDAC8降解剂作为尤文肉瘤的新候选治疗药物。 儿童和年轻人的侵袭性癌症，迫切需要新的治疗方案。第二， 我们希望开发选择性的HDAC6降解物来测试HDAC6在炎症小体激活中的作用。 我们相信，这一策略广泛适用于其他蛋白质家族，并将对 发展降解剂疗法的领域。

Project Summary Targeted protein degradation with small molecule degraders is an emerging therapeutic modality for cancer treatment. Degraders have several advantages compared with traditional inhibitor drugs that make them attractive new therapeutic entities. First, degraders can work at much lower concentration than inhibitors, thus can be used at lower dosage and have lower drug toxicity. Second, degraders remove the target protein altogether rather than simply inhibiting the enzymatic activity of the protein, thus eliminating the non-enzymatic activities of target proteins. Such non-enzymatic activities are especially common for histone deacetylases (HDACs). Third, degraders can be used to target targets considered “undruggable” by conventional means, which represent 80% of the human proteome, as long as a protein binding ligand is available. However, the current strategies to develop degraders follow a rather empirical route with fortuitous outcomes. Here we propose to develop a new screening platform to discover and develop degrader molecules. The strategy involves structure guided degrader library design based on promiscuous inhibitors that target a protein family followed by chemo-proteomics screening to identify degradable protein family members and selective degraders against them. The large amount of data from proteomics screens enables us to understand the relationship between the chemical structures of degraders and potency of target protein degradation, which feeds back to the next round of iterative library design and screening. Such iterative rounds of optimization with proteomics evaluation have proven to be a more effective way to generate selective and potent degraders for developing therapeutic candidates and chemical probes for biological studies. We apply this strategy to an important family of enzymes, HDACs, for which specific inhibitors are rarely available. HDACs are therapeutic targets for many different kinds of cancer and human diseases. We propose to develop selective degraders for a number of HDAC members. Particularly, we hope to develop HDAC8 degraders as a new therapeutic candidate for Ewing sarcoma, an aggressive cancer in children and young adults that have an urgent need for new therapeutic options. Secondly, we hope to develop selective HDAC6 degraders to test the proposed role of HDAC6 in inflammasome activation. We believe this strategy is widely applicable to other protein families and would make a significant impact in the field of developing degrader therapeutics.