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

开发适用于 HDAC 的小分子降解剂的通用化学蛋白质组学筛选平台

• 批准号: 10442847
• 负责人: Eric Sebastian Fischer
• 金额: $ 48.72万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-07 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442847
• 关键词: Address; Antineoplastic Agents; Back; Binding Proteins; Biological; Biological Assay; Biology; CUL2 gene; Cell Death; Cell Line; Chemical Structure; Chemicals; Communities; Complex; Data; Dependence; Development; Docking; Drug Targeting; Drug toxicity; Enzymes; Evaluation; Ewings sarcoma; Exhibits; Family; Family member; Feeds; Genetic; Goals; HDAC6 gene; HDAC8 gene; Health; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; In Vitro; Inflammasome; Lead; Leukemic Cell; Libraries; Ligands; Ligase; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Methods; Modality; Nature; Nuclear Hormone Receptors; Outcome; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Play; Process; Property; Protein Family; Proteins; Proteome; Proteomics; RBX1 gene; Research; Role; Route; Scaffolding Protein; Structure; Testing; Therapeutic; Ubiquitination; Work; assay development; base; cancer therapy; cell killing; chemoproteomics; clinical development; design; dosage; drug development; drug discovery; human disease; in vivo; inhibitor; inhibitor therapy; interest; lead optimization; member; mutant; novel; novel therapeutics; protein degradation; recruit; screening; small molecule; small molecule libraries; success; synergism; therapeutic candidate; therapeutic target; tool; transcription factor; translational potential; ubiquitin-protein ligase; young adult

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.

项目摘要 用小分子降解剂靶向蛋白质降解是一种新兴的癌症治疗方式 治疗与传统的抑制剂药物相比，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起作用， 可以以较低的剂量使用，药物毒性较低。第二，降解剂去除目标蛋白 而不是简单地抑制蛋白质的酶活性，从而消除了非酶活性。 目标蛋白的活性。这样的非酶活性对于组蛋白脱乙酰酶来说尤其常见 （HDAC）。第三，降能器可用于以常规手段瞄准被认为是“不可药”的目标， 其代表80%的人类蛋白质组，只要蛋白质结合配体可用。但 目前开发降解物的战略遵循一种相当经验性的路线，结果是偶然的。在这里我们建议 开发一个新的筛选平台来发现和开发降解分子。本战略涉及 基于靶向蛋白质家族的混杂抑制剂的结构引导降解剂库设计，然后 化学蛋白质组学筛选，以鉴定可降解蛋白质家族成员和选择性降解剂， 他们来自蛋白质组学筛选的大量数据使我们能够了解蛋白质组学之间的关系。 降解物的化学结构和靶蛋白降解的效力，其反馈到下一轮 迭代的文库设计和筛选。这种迭代的优化与蛋白质组学评估， 被证明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 生物学研究的候选人和化学探针。我们将这种策略应用于一个重要的酶家族， HDAC，其特异性抑制剂很少可用。HDAC是许多不同类型的治疗靶点 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HDAC 8降解剂作为尤文肉瘤的新治疗候选药物， 儿童和年轻人的侵袭性癌症，迫切需要新的治疗选择。第二、 我们希望开发选择性HDAC 6降解剂以测试HDAC 6在炎性小体活化中的作用。 我们相信这种策略广泛适用于其他蛋白质家族，并将对蛋白质家族产生重大影响。 开发降解剂疗法的领域。