Expanding the scope of protein degradation and stability using chemoproteomic platforms

使用化学蛋白质组平台扩大蛋白质降解和稳定性的范围

• 批准号: 10373160
• 负责人: Carl ward
• 金额: $ 8.72万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10373160
• 关键词: Address; Antineoplastic Agents; Award; Binding; Chemicals; Complex; Environment; Fellowship; Glues; Goals; Grant; Impairment; Institution; International; Interview; Knowledge; Lead; Ligands; Link; Malignant Neoplasms; Maps; Mentors; Mining; Molecular; Paper; Pathogenicity; Pharmacology; Phase; Positioning Attribute; Postdoctoral Fellow; Proteins; Proteome; Proteomics; Public Speaking; Research; Research Project Grants; Resources; Site; Technology; Thalidomide; Therapeutic; Time; Tumor Suppressor Proteins; Writing; activity-based protein profiling; base; cancer cell; cancer therapy; cancer type; chemoproteomics; drug discovery; graduate student; lenalidomide; notch protein; novel anticancer drug; novel therapeutics; professor; protein degradation; protein function; receptor; recruit; responsible research conduct; screening; skills; small molecule; success; symposium; targeted cancer therapy; technological innovation; tenure track; ubiquitin-protein ligase

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.

靶向蛋白质降解(TPD)作为一个强大的药物发现平台已经出现，以应对 通过形成靶向蛋白酶体降解的特定蛋白的不可下药的蛋白质组 由小分子分子胶或异双功能降解剂促进的三元络合物 将E3泛素连接酶与新底物蛋白结合在一起。虽然这种方法在 在癌症药物发现中的受欢迎程度，一个主要挑战包括E3连接酶招聘人员的缺乏，尽管 &gt；600 E3连接酶的丰富，以及极少数的分子胶和neo- 用于降解的底物。TPD的另一个挑战是它不能应用于蛋白质底物 就像癌细胞中的许多肿瘤抑制因子一样，它们被活跃地泛素化和降解。要解决这两个问题 挑战，我建议利用化学蛋白质组学启用的共价配体发现平台来 发现用于TPD应用的新E3连接酶招募者并开发新的抗癌药物发现 靶向蛋白稳定(TPS)用于去泛素化和稳定肿瘤的范例 抑制者，通过发现和应用脱泛素酶招募者。化学蛋白质组学 基于活动的蛋白质图谱(ABPP)等平台已经作为绘制地图的强大平台而兴起 和药理学靶向蛋白质组广泛的配基部位。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、可配位性和功能性部位。在这里，我会 使用ABPP发现针对E3连接酶和脱泛素酶的共价配体库，这些配基可以 适用于TPD和TPS。 在我的F99研究生论文阶段，我将通过发现以下内容来扩大TPD的范围 新的E3连接酶招募者，可用于蛋白质酶降解癌症治疗目标。在此期间，我 我还会参加国内和国际会议，磨练我的指导技能，参加负责任的课程 进行研究，磨练我的论文和论文写作技能，以及面试博士后职位 扩大我的知识面，建立关系网，并找到一个最佳的博士后职位。我的研究生研究 加州大学伯克利分校和野村研究集团的环境是一流的，在那里我可以接触到世界级的 教授，并与顶尖研究生和博士后研究员互动，以及 尖端技术和资源。在我的K00阶段，我将推进TPS平台，以开发新的 稳定抑癌基因表达以发展新型癌症的药物发现范式 心理治疗。在此期间，我还将继续参加国内和国际会议，磨练我的技能 辅导，论文和资助写作，以及公开演讲，申请K99/R00过渡奖，并申请 顶尖研究机构的终身教授职位。