Using chemoproteomic approaches to expand upon induced-proximity modalities for cancer therapy

使用化学蛋白质组学方法扩展癌症治疗的诱导接近模式

• 批准号: 10064949
• 负责人: Jessica Nichole Spradlin
• 金额: $ 4.31万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-17 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064949
• 关键词: Acetyltransferase; Antineoplastic Agents; Binding; Chimera organism; Cysteine; DNA; Data; Deacetylase; Drug Industry; Enzymes; Explosion; Face; Future; Libraries; Ligands; Link; Malignant Neoplasms; Mediating; Modality; Natural Products; Phase; Phosphoric Monoester Hydrolases; Phosphotransferases; Post-Translational Protein Processing; Protac; Proteins; Proteome; Research; Research Project Grants; System; Technology; Testing; Therapeutic; Ubiquitin; activity-based protein profiling; base; cancer therapy; chemoproteomics; drug discovery; inhibitor/antagonist; innovative technologies; interest; multicatalytic endopeptidase complex; novel; novel therapeutics; protein degradation; recruit; screening; small molecule; ubiquitin-protein ligase

One of the biggest challenges that we face in discovering new cancer therapies is that most proteins are considered “undruggable,” in that most proteins do not possess known binding pockets or “druggable hotspots” that can be functionally targeted with small-molecules using traditional drug discovery paradigms 1. This grand challenge of tackling the undruggable proteome has catalyzed the explosion of innovative technologies that enable unique access into the functional targeting of biomolecules for drug discovery or new “druggable modalities.” Examples of some of these small- molecule based technologies include chemoproteomics-enabled covalent ligand screening using activity-based protein profiling (ABPP) and DNA-encoded library platforms for discovering functional or non-functional ligands against undruggable proteins, and proteolysis-targeting chimeras (PROTACs) that use heterobifunctional molecules for recruitment of E3 ligases for targeted ubiquitin-proteasome system-dependent degradation of specific proteins. Each of these approaches facilitate the discovery of small-molecules that access classically intractable cancer targets in a unique manner. While interest in these technologies have exploded in recent years in the pharmaceutical industry, the small- molecule mediated induced proximity modalities (IPMs), such as PROTACs, are just the tip of the iceberg of yet undiscovered IPMs for cancer drug discovery. In my graduate research thus far, I used chemoproteomic approaches to discover that the covalently-acting natural product nimbolide targeted a cysteine within a substrate recognition domain of the E3 ubiquitin ligase RNF114, and that nimbolide could be exploited as a new E3 ligase recruiter for PROTAC applications. In the F99 phase of my proposal, I plan to characterize the broad utility of nimbolide and other fully synthetic RNF114 recruiters for PROTAC applications in the F99 phase of my proposal. In the K00 phase of my proposal, I plan to develop new heterobifunctional IPM paradigms, namely Kinase-Targeting Chimeras (KinaTACs), Phosphatase-Targeting Chimeras (PhosphaTACs), Acetyltransferase-Targeting Chimeras (ATTACs), and Deacetylase-Targeting Chimeras (DATACs) using chemoproteomics-enabled covalent ligand discovery platforms, towards developing new therapeutic modalities for cancer therapy.

我们发现新的癌症疗法面临的最大挑战之一是，大多数蛋白质都被认为 “不可用”，因为大多数蛋白质都不拥有已知的结合口袋或“可药的热点” 使用传统药物发现范式1。 不良蛋白质组的不良蛋白质组催化了创新技术的爆炸，使独特的访问能够进入 用于药物发现或新的“可药物方式”的生物分子的功能靶向。其中一些小的例子 基于分子的技术包括使用基于活性的基于活性的化学蛋白质组学共价配体筛选 蛋白质分析（ABPP）和DNA编码的库平台，用于发现针对的功能或非功能配体 不良蛋白质和蛋白水解靶向嵌合体（protac），使用异常分子进行 募集E3连接酶，用于靶向泛素 - 蛋白酶体系统依赖性蛋白质的降解。每个 这些方法有助于发现小分子，这些小分子以独特的方式进入经典的癌症目标 方式。尽管对这些技术感兴趣，但近年来在制药行业探索了这些技术，但小型 分子介导的诱导近端方式（IPM），例如Protac，只是冰山一角 未发现的癌症药物发现IPM。到目前为止，在我的研究生研究中，我使用化学蛋白质组学方法来 发现共价作用的天然产物Nimbolide针对的是在底物识别域内的半胱氨酸 E3泛素连接酶RNF114，并且可以将Nimbolide探索为Protac的新型E3连接酶招聘器 申请。在我的提案的F99阶段，我计划表征Nimbolide和其他全部的广泛效用 在我的提案的F99阶段，用于Protac应用的合成RNF114招聘器。在我的K00阶段 提案，我计划开发新的异性功能IPM范式，即激酶靶向嵌合体 （KINATACS），磷酸酶靶向嵌合体（磷酸酯），乙酰转移酶靶向嵌合体（ATTACS）， 使用启用化学蛋白质组学的配体发现的脱乙酰基酶靶向嵌合体（数据） 平台，以开发用于癌症治疗的新治疗方式。

项目成果

Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function.

• DOI: 10.1016/j.chembiol.2021.01.005
• 发表时间: 2021-04-15
• 期刊: Cell chemical biology
• 影响因子: 8.6
• 作者: Luo M;Spradlin JN;Boike L;Tong B;Brittain SM;McKenna JM;Tallarico JA;Schirle M;Maimone TJ;Nomura DK
• 通讯作者: Nomura DK