Targeted Protein Stabilization Platforms

靶向蛋白质稳定平台

基本信息

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
项目类别：
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

项目摘要

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.

开发新的癌症疗法的主要挑战是，大多数蛋白质组的大多数（> 90％）被认为 “不可能。”这意味着大多数蛋白质没有特征性的功能结合口袋，或小分子可以结合以调节蛋白质的功能以使治疗益处调节功能。因此，开发新的疾病疗法需要新颖的治疗方式和药物发现揭示新的独特方法来改变传统“不良”蛋白质的蛋白质功能的范例。靶向蛋白质降解（TPD）使用涉及蛋白水解的嵌合体（Protac）已成为强大的通过靶向特定蛋白质以泛素化和蛋白酶体降解。 protac，由靶向蛋白质靶向的异质功能小分子配体与E3连接酶招聘器相关，通过诱导的三元络合物的形成来起作用 E3泛素连接酶，具有新的基质蛋白靶靶兴趣。虽然TPD是一个非常强大的平台，可在细胞，有许多蛋白质积极地泛素化并降解以引起疾病。在这些情况下，靶向蛋白质的去泛素化和稳定而不是降解，可以代表一种可行的治疗战略。积极泛素化和降解以引起疾病发病机理的蛋白质包括肿瘤补充剂TP53，CDKN1A（P21），CDKN1C（p57），癌症中的Bax和Axin或囊性突变体CFTR 通过去泛素化对这些蛋白质稳定的纤维化可能是有益的。开发用于靶向蛋白质稳定（TPS）的靶向嵌合体（DUBTAC）平台的去泛素酶将去泛素酶（DUB）招聘者与靶向蛋白质靶向配体连接的异常小分子将启用一种新的热模式，以稳定和增加蛋白酶体的表达蛋白质。在此建议中，我将利用启用化学蛋白质组学的共价探索平台通过将DUB招募到特定的Neo-Substrates来开发TPS的DUBTAC平台蛋白质靶标的去泛素化和稳定为治疗益处。