Chemical Proteomics Approach to Discover Novel Small Molecule E3 Ligase recruiters for Targeted Protein degradation (TPD)

化学蛋白质组学方法发现用于靶向蛋白质降解 (TPD) 的新型小分子 E3 连接酶招募剂

• 批准号: 10711249
• 负责人: Jaewon Chang
• 金额: $ 39.13万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711249
• 关键词: Chemicals; Chemistry; Coupled; Cysteine; Development; Disease; Goals; Human Genome; Ligands; Lysine; Modality; Molecular; Protein Degradation Induction; Proteins; Proteomics; Publishing; Research; Series; Serine; Tacrolimus Binding Protein 1A; Therapeutic; Tissues; Tyrosine; Ubiquitination; adduct; biomaterial compatibility; chemoproteomics; design; interest; next generation; novel; novel strategies; novel therapeutics; pharmacologic; protein degradation; recruit; small molecule; ubiquitin-protein ligase

Project Summary Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to overcome limitations of traditional pharmacological inhibition approaches. TPD uses small molecules (degraders) to hijack the cellular degradation machinery by recruiting E3 ubiquitin ligases to proteins of interest (POI), which would not otherwise be recognized as substrate. Despite the tremendous promise of TPD approach, major bottlenecks still exist, including: 1) ligand discovery against undruggable disease-causing proteins. 2) a dearth of available E3 ligase recruiters that can be exploited for TPD applications, as there are limited number of E3 ligases, with most of the published degraders using ligands for cereblon and VHL, despite the existence of >600 E3 ligases in the human genome. Therefore, it is a great deal of interest in the discovering of new E3 ligase ligands to expand the scope of new therapeutics. Recently, several research groups discovered cysteine-reactive covalent recruiters against previously untargeted E3 ligases that have been successfully used in TPD by using chemical proteomic approaches. While targeting cysteines serves as a useful starting point, there is a need to consider other types of chemistry to generate covalent E3 recruiters for targeting new E3 ligases to expand the scope of TPD. One such possibility is to target potential nucleophilic residue, such as lysine, tyrosine, and serine on E3 ligases, respectively. However, specific biocompatible electrophiles targeting lysines, tyrosine, and serine are largely unexplored for TPD application. The ultimate goal of this proposal is to design, synthesize and validate new E3 ligases ligands that enable the development of novel degraders. To achieve this, we will use a chemoproteomic strategy that leverages broadly reactive, lysine, tyrosine, and serine-directed electrophilic warheads coupled to selective ligands for intracellular proteins (JQ1 for BRD4 or SLF for FKBP12) to screen for heterobifunctional degrader compounds that operate by covalent adduction of E3 ligases. To this end, we have already succeeded in developing a series of compounds to promote ligand-induced protein degradation. These proof-of-concept degraders led to the induced ubiquitination and proteasomal degradation of target proteins. We will perform further chemoproteomic studies to identify the E3 ligase targets of these degraders responsible for the degradation activity. With our novel approaches, we expect to see the repertoire of E3 ligases recruited for targeted protein degradation to be further enriched, paving the way for the next generation of tissue- and disease- specific molecular degraders.

项目摘要 靶向蛋白质降解（TPD）是一种新兴的治疗方式，有可能克服 传统药理抑制方法的局限性。 TPD使用小分子（降解器）来劫持 通过将E3泛素连接酶募集到感兴趣的蛋白质（POI）的细胞降解机械，这将 否则不被识别为底物。尽管TPD方法有很大的希望，但主要的瓶颈 仍然存在，包括：1）针对不良疾病蛋白质的配体发现。 2）缺乏可用的 可以利用用于TPD应用的E3连接酶招聘器，因为E3连接次数有限，并且 尽管存在> 600 E3连接酶，但大多数使用配体使用配体用于Cereblon和VHL的降解器 在人类基因组中。因此，对于发现新的E3连接配体的兴趣是很大的兴趣 扩大新疗法的范围。最近，一些研究小组发现半胱氨酸反应性共价 招聘人员反对以前未靶向的E3连接酶，这些连接酶已通过化学成功地用于TPD 蛋白质组学方法。靶向半胱氨酸是一个有用的起点，但有必要考虑 其他类型的化学反应生成共价E3招聘者，以瞄准新的E3连接酶以扩大范围 TPD。一种可能性是靶向潜在的亲核残基，例如赖氨酸，酪氨酸和丝氨酸在E3上 连接酶分别。但是，靶向赖氨酸，酪氨酸和丝氨酸的特定生物相容性的电力是 对于TPD应用程序，在很大程度上未探索。该建议的最终目标是设计，合成和验证 新的E3连接配体可以使新型降解器的发展。为了实现这一目标，我们将使用 化学蛋白质组学策略，该策略利用了广泛反应性，赖氨酸，酪氨酸和丝氨酸指导的亲电的策略 弹头与细胞内蛋白的选择性配体（BRD4的JQ1或FKBP12的SLF）筛选以筛选 通过共价添加E3连接酶操作的异质功能降解器化合物。为此，我们有 已经成功地开发了一系列化合物，以促进配体诱导的蛋白质降解。这些 概念证明降解者导致靶蛋白的泛素化和蛋白酶体降解。我们 将进行进一步的化学蛋白质组学研究，以识别负责这些降解者的E3连接酶靶标 降解活动。通过我们的新方法，我们希望看到E3连接酶的曲目 靶向蛋白质降解将进一步富集，为下一代组织和疾病铺平了道路 特定的分子降解器。