Expanding the scope of protein degradation and stability using chemoproteomic platforms

靶向蛋白质降解（TPD）已经成为一个强大的药物发现平台，用于解决 通过靶向蛋白酶体降解的特定蛋白质， 三元复合物由小分子分子胶或异双功能降解剂促进， 使E3泛素连接酶与新底物蛋白结合。虽然这种方法在 在癌症药物发现中的流行，一个主要的挑战包括缺乏E3连接酶招募者，尽管 丰富的>600 E3连接酶，以及分子胶和新- 降解底物。TPD的另一个挑战是它不能应用于蛋白质底物， 在癌细胞内像许多肿瘤抑制因子一样被积极地泛素化和降解。为了解决这两 挑战，我建议利用化学蛋白质组学使共价配体发现平台， 为TPD应用发现新的E3连接酶招募者，并开发新的癌症药物发现 用于去泛素化和稳定肿瘤的靶向蛋白稳定化（TPS）的范例 抑制剂，通过发现和应用去泛素化酶招募。化学蛋白质组学 平台，如基于活性的蛋白质谱（ABPP），已经成为强大的平台，以映射 和靶向蛋白质组范围内的可配位位点。ABPP使用基于反应性的化学探针 直接在复杂蛋白质组中分析蛋白质组范围内的反应性、可配体和功能性位点。来，我来 利用ABPP发现了一个针对E3连接酶和去泛素化酶的共价配体库， 适用于TPD和TPS。 在F99研究生论文阶段，我将通过发现 新的E3连接酶募集剂，可用于蛋白酶体降解癌症治疗靶点。这段时间我 我还将参加国家和国际会议，磨练我的指导技能，参加课程，负责 研究行为，磨练我的论文和拨款写作技能，并面试博士后职位， 扩展我的知识，网络，并找到一个最佳的博士后职位。我的研究生研究 在加州大学伯克利分校和野村研究集团，我的环境是一流的，在那里我可以接触到世界一流的 教授，并与一流的研究生和博士后研究员互动，以及切割 边缘技术和资源。在我的K 00阶段，我将推进TPS平台， 用于稳定肿瘤抑制因子表达以开发新型癌症的药物发现范例 疗法在此期间，我还将继续参加国家和国际会议，磨练我的技能， 指导，论文和资助写作，以及公开演讲，申请K99/R 00过渡奖，并申请 顶级研究机构的终身教授职位。

Targeted protein degradation (TPD) has arisen as a powerful drug discovery platform for tackling the undruggable proteome by targeting specific proteins for proteasomal degradation through the formation of ternary complexes facilitated by either small-molecule molecular glues or heterobifunctional degraders that bring together an E3 ubiquitin ligase with a neo-substrate protein. While this approach has exploded in popularity in cancer drug discovery, a major challenge includes the dearth of E3 ligase recruiters despite the abundance of >600 E3 ligases, and the very few examples of molecular glues and recruitment of neo- substrates for degradation. Another challenge of TPD is that it cannot be applied to protein substrates which are actively ubiquitinated and degraded like many tumor suppressors within cancer cells. To address these two challenges, I propose to utilize chemoproteomics-enabled covalent ligand discovery platforms to discover new E3 ligase recruiters for TPD applications and develop a new cancer drug discovery paradigm for targeted protein stabilization (TPS) for deubiquitinating and stabilizing tumor suppressors, through the discovery and application of deubiquitinase recruiters. Chemoproteomic platforms, such as activity-based protein profiling (ABPP), have arisen as powerful platforms to mapping and pharmacologically targeting proteome-wide ligandable sites. ABPP uses reactivity-based chemical probes to profile proteome-wide reactive, ligandable, and functional sites directly in complex proteomes. Here, I will use ABPP to discover an arsenal of covalent ligands against E3 ligases and deubiquitinases that can be applied for TPD and TPS. During the F99 graduate thesis phase of my fellowship, I will expand the scope of TPD by discovering new E3 ligase recruiters that can be used to proteasomally degrade cancer therapy targets. During this time, I will also attend national and international conferences, hone my skills in mentoring, take courses in responsible research conduct, hone my skills in paper and grant writing, and interview for postdoctoral positions towards expanding my knowledge, networking, and finding an optimal postdoctoral position. My graduate research environment is stellar at UC Berkeley and in the Nomura Research Group, where I have access to world-class professors and have interactions with top-notch graduate students and postdoctoral fellows, as well as cutting edge technologies and resources. During my K00 phase, I will advance the TPS platform to develop a new drug discovery paradigm for stabilizing the expression of tumor suppressors to develop a new type of cancer therapy. During this time, I will also continue to attend national and international conferences, hone my skills in mentoring, paper and grant writing, and public speaking, apply for the K99/R00 transition award, and apply for tenure-track professor positions at top-tier research institutions.