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 靶向蛋白降解(TPD)是一种新兴的治疗方法，具有克服 传统药物抑制方法的局限性。TPD使用小分子(降解物)劫持 通过将E3泛素连接酶招募到感兴趣蛋白(POI)来实现细胞降解机制，这将 否则不被认为是底物。尽管TPD方法前景看好，但主要瓶颈 仍然存在，包括：1)发现针对不可药物致病蛋白的配体。2)可用资源的匮乏 可用于TPD应用的E3连接酶招募者，因为E3连接酶的数量有限， 尽管&gt；600 E3连接酶的存在，但大多数已发表的降解物仍使用Cereblon和VHL的配体 在人类基因组中。因此，发现新的E3连接酶配体是非常有兴趣的 扩大新疗法的应用范围。最近，几个研究小组发现半胱氨酸-反应性共价 招聘人员对照以前未被靶向的E3连接酶，这些连接酶已通过使用化学物质成功地用于TPD 蛋白质组学方法。虽然以半胱氨酸为目标是一个有用的起点，但有必要考虑 其他类型的化学，以产生共价E3招募者为目标的新的E3连接酶，以扩大范围 TPD。一种这样的可能性是将潜在的亲核残基，如赖氨酸、酪氨酸和丝氨酸靶向E3。 分别为连接酶。然而，以赖氨酸、酪氨酸和丝氨酸为靶点的特定生物兼容亲电体 对于TPD应用，很大程度上是未开发的。该方案的最终目标是设计、综合和验证 能够开发新型降解物的新的E3配体。为了实现这一点，我们将使用 利用广泛的反应性、赖氨酸、酪氨酸和丝氨酸导向的亲电作用的化学蛋白质组策略 与细胞内蛋白的选择性配体(BRD4的JQ1或FKBP12的SLF)连接的弹头用于筛选 通过E3连接酶的共价加成起作用的异双功能降解物。为此，我们有 已经成功开发了一系列化合物来促进配体诱导的蛋白质降解。这些 概念验证降解物导致目标蛋白的诱导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，以确定这些降解物的E3连接酶靶标 降解活性。通过我们的新方法，我们希望看到E3连接酶库被招募用于 有针对性的蛋白质降解将进一步丰富，为下一代组织和疾病铺平道路- 特定的分子降解剂。