Targeted Protein Stabilization Platforms

靶向蛋白质稳定平台

• 批准号: 10379626
• 负责人: Nathaniel James Henning
• 金额: $ 2.51万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379626
• 关键词: Acrylamides; Apoptosis; BAX gene; Binding; Biological Assay; Biology; CDKN1A gene; CDKN1C gene; Cell model; Cells; Chimera organism; Chloride Channels; Complex; Cysteine; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Databases; Deubiquitination; Development; Disease; Epithelial Cells; Goals; Human; Label; Length; Libraries; Ligands; Link; Malignant Neoplasms; Maps; Mediating; Membrane; Mining; Modality; Pathogenesis; Pharmaceutical Preparations; Pharmacology; Protac; Proteins; Proteome; Proteomics; Recombinant Proteins; Recombinants; Research; TP53 gene; Therapeutic; Tumor Suppressor Proteins; Ubiquitin; Ubiquitination; activity-based protein profiling; base; bronchial epithelium; cancer cell; cancer therapy; chemoproteomics; cystic fibrosis patients; drug discovery; interest; multicatalytic endopeptidase complex; mutant; novel therapeutics; protein degradation; protein function; recruit; small molecule; targeted treatment; technological innovation; trafficking; ubiquitin-protein ligase

A major challenge in developing new cancer therapies is that most, >90 %, of the proteome is considered “undruggable.” This implies that most proteins are devoid of characterized, functional binding pockets, or “druggable hotspots,” that small molecules can bind to modulate a protein’s function for therapeutic benefit. Developing new disease therapies therefore requires novel therapeutic modalities and drug discovery paradigms for uncovering new, unique ways to alter protein function of traditionally “undruggable” proteins. Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) has arisen as a powerful modality for tackling the undruggable proteome by targeting specific proteins for ubiquitination and proteasomal degradation. PROTACs, heterobifunctional small molecules consisting of a protein-targeting ligand linked to an E3 ligase recruiter, act through inducing formation of ternary complexes that bring together an E3 ubiquitin ligase with a neo-substrate protein target to polyubiquitinate and degrade specific targets of interest. While TPD is an incredibly powerful platform for degrading potentially any disease-causing protein in cells, there are many proteins that are actively ubiquitinated and degraded to cause disease. In these cases, targeted protein deubiquitination and stabilization, instead of degradation, could represent a viable therapeutic strategy. Proteins that are actively ubiquitinated and degraded to cause disease pathogenesis include tumor suppressors TP53, CDKN1A (p21), CDKN1C (p57), BAX, and axin in cancer, or mutant CFTR in cystic fibrosis, and stabilization of these proteins through deubiquitination could be beneficial. Developing a Deubiquitinase Targeting Chimera (DubTAC) platform for targeted protein stabilization (TPS) that utilizes heterobifunctional small molecules linking deubiquitinase (DUB) recruiters to protein-targeting ligands would enable a new therapeutic modality for stabilizing and increasing expression of proteasomally-degraded proteins. In this proposal I will utilize chemoproteomics-enabled covalent ligand discovery platforms to develop a DubTAC platform for TPS, through recruiting DUBs to specific neo-substrates for targeted deubiquitination and stabilization of protein targets for therapeutic benefit.

开发新癌症疗法的一个主要挑战是大多数（>90%）的蛋白质组被认为是 “无法成药。”这意味着大多数蛋白质缺乏特征性的、功能性的结合袋，或者 “可成药热点”，即小分子可以结合来调节蛋白质的功能以获得治疗效果。 因此，开发新的疾病疗法需要新的治疗方式和药物发现 揭示新的、独特的方法来改变传统上“不可成药”蛋白质的蛋白质功能的范例。 使用蛋白水解靶向嵌合体 (PROTAC) 进行靶向蛋白质降解 (TPD) 已成为一种强大的 通过靶向特定蛋白质进行泛素化来解决不可成药的蛋白质组的方式 蛋白酶体降解。 PROTAC，由蛋白质靶向组成的异双功能小分子 与 E3 连接酶募集剂连接的配体，通过诱导形成三元复合物来发挥作用，将三元复合物聚集在一起 一种 E3 泛素连接酶，具有新底物蛋白靶标，可多泛素化并降解特定靶标 兴趣。虽然 TPD 是一个非常强大的平台，可以降解体内任何潜在的致病蛋白质。 细胞中，有许多蛋白质被主动泛素化和降解从而导致疾病。在这些情况下， 靶向蛋白质去泛素化和稳定化而不是降解可能是一种可行的治疗方法 战略。主动泛素化和降解导致疾病发病机制的蛋白质包括肿瘤 癌症中的抑制因子 TP53、CDKN1A (p21)、CDKN1C (p57)、BAX 和 axin，或囊性囊肿中的突变 CFTR 纤维化以及通过去泛素化稳定这些蛋白质可能是有益的。开发一个 去泛素酶靶向嵌合体 (DubTAC) 平台用于靶向蛋白质稳定 (TPS)，利用 将去泛素酶（DUB）招募分子与蛋白质靶向配体连接起来的异双功能小分子将 提供一种新的治疗方式来稳定和增加蛋白酶体降解的表达 蛋白质。在本提案中，我将利用化学蛋白质组学支持的共价配体发现平台来 通过将 DUB 招募到特定的新基质上，开发用于 TPS 的 DubTAC 平台 蛋白质靶标的去泛素化和稳定化以获得治疗益处。