Targeted Protein Stabilization Platforms

开发新的癌症疗法的一个主要挑战是，大多数，> 90%，蛋白质组被认为是 "无法抗拒"这意味着大多数蛋白质缺乏特征性的功能性结合口袋，或 “可用药热点”，即小分子可以结合以调节蛋白质的功能以获得治疗益处。 因此，开发新的疾病疗法需要新的治疗方式和药物发现 发现新的，独特的方法来改变传统的“不可药用”蛋白质的蛋白质功能的范例。 使用蛋白水解靶向嵌合体（PROTAC）的靶向蛋白降解（TPD）已经作为一种强大的生物降解方法而出现。 通过靶向特定蛋白质进行泛素化来处理不可治疗的蛋白质组的模式， 蛋白酶体降解PROTAC，由蛋白质靶向的异双功能小分子组成 与E3连接酶募集物连接的配体，通过诱导三元复合物的形成起作用， 具有新底物蛋白的E3泛素连接酶靶向聚泛素化并降解 兴趣虽然TPD是一个非常强大的平台，可以降解潜在的任何致病蛋白质， 在细胞中，有许多蛋白质被活跃地泛素化和降解以引起疾病。在这些情况下， 靶向蛋白去泛素化和稳定化，而不是降解，可能代表一种可行的治疗方法， 战略被主动泛素化和降解以引起疾病发病机制的蛋白质包括肿瘤 肿瘤中的TP53、CDKN1A（p21）、CDKN1C（p57）、BAX和axin抑制因子，或囊性癌中的突变CFTR抑制因子。 纤维化和通过去泛素化稳定这些蛋白质可能是有益的。开发一 用于靶向蛋白稳定化（TPS）的去泛素化酶靶向嵌合体（DubTAC）平台， 将去泛素化酶（DUB）募集剂连接到蛋白质靶向配体的异双功能小分子将 能够稳定和增加蛋白酶体降解的 proteins.在这项提案中，我将利用化学蛋白质组学使能的共价配体发现平台， 为TPS开发DubTAC平台，通过招募DUB到特定的新底物， 去泛素化和稳定蛋白质靶标以获得治疗益处。

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.