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: 10640286
• 负责人: Eric Sebastian Fischer
• 金额: $ 44.68万
• 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/10640286
• 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; HDAC4 gene; 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; Phosphotransferases; Play; Process; Property; Protein Degradation Induction; Protein Family; Proteins; Proteome; Proteomics; RBX1 gene; Research; Role; Route; Scaffolding Protein; Structure; Testing; Therapeutic; Ubiquitination; Work; assay development; 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; pharmacologic; 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 靶向蛋白质降解与小分子降解器是一种新兴的癌症治疗方式 治疗。与传统抑制剂药物相比，降级器具有多个优势 有吸引力的新治疗实体。首先，降解器的浓度比抑制剂低得多，因此 可用于较低剂量，并具有较低的药物毒性。其次，降解器去除目标蛋白 完全不简单地抑制蛋白质的酶活性，从而消除非酶 靶蛋白的活性。这种非酶活性对于组蛋白脱乙酰基酶特别常见 （HDACS）。第三，降级器可用于通过常规方式被认为“不良困难”的目标， 只要可以使用蛋白质结合，它代表了人类蛋白质的80％。但是， 当前开发降级者的策略遵循一条相当经验的途径，并具有偶然的结果。我们在这里提出 开发一个新的筛选平台来发现和开发降解分子。策略涉及 结构以降级器库设计为基于缔合蛋白家族的混杂抑制剂，然后 化学蛋白质组学筛查以鉴定可降解的蛋白质家族成员和选择性降解者针对 他们。来自蛋白质组学的大量数据使我们能够了解 降解器的化学结构和靶蛋白降解的效力，该结构回到下一轮 迭代库设计和筛选。通过蛋白质组学评估进行优化的迭代回合已有 被证明是产生选择性和潜在降解者开发治疗的一种更有效的方法 生物学研究的候选和化学问题。我们将此策略应用于重要的酶家族， HDAC，很少有特定抑制剂。 HDAC是许多不同种类的热目标 癌症和人类疾病。我们建议为许多HDAC成员开发选择性降级器。 特别是，我们希望将HDAC8 DEGRADERS开发为Ewing Sarma的新治疗候选者， 迫切需要新的治疗选择的儿童和年轻人的侵略性癌症。第二， 我们希望开发选择性HDAC6降解器，以测试HDAC6在炎性体激活中提出的作用。 我们认为，该策略广泛适用于其他蛋白质家族，将对 发展降解者疗法的领域。

项目成果

HDAC6/aggresome processing pathway importance for inflammasome formation is context dependent.

HDAC6/聚集体加工途径对炎症小体形成的重要性取决于环境。

• DOI: 10.1101/2023.08.15.553363
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Wang,Longlong;Unterreiner,Adeline;Kapetanovic,Ronan;Aslani,Selma;Xiong,Yuan;Donovan,KatherineA;Farady,ChristopherJ;Fischer,EricS;Bornancin,Frédéric;Matthias,Patrick
• 通讯作者: Matthias,Patrick