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

我们在发现新的癌症疗法时面临的最大挑战之一是大多数蛋白质被认为是 “不能下药”，因为大多数蛋白质不具有已知的结合口袋或“可下药的热点”。 使用传统药物发现范式以小分子为功能靶点1.这一重大挑战 这种无法下药的蛋白质组催生了创新技术的爆炸，使人们能够以独特的方式进入 生物分子的功能靶向用于药物发现或新的“可用药模式”。其中一些小的例子- 基于分子的技术包括使用基于活性的化学蛋白质组学启用的共价配体筛选 蛋白质图谱(ABPP)和DNA编码库平台，用于发现功能性或非功能性配体 不能下药的蛋白质，以及使用异双功能分子进行蛋白质降解的嵌合体(PROTAC) E3连接酶的募集用于特定蛋白质的靶向泛素-蛋白酶体系统依赖的降解。每一个 这些方法促进了小分子的发现，这些小分子可以在独特的 举止。虽然近年来制药业对这些技术的兴趣激增，但小型- 分子介导的诱导邻近模式(IPMS)，如PROTAC，还只是冰山一角 未发现的用于抗癌药物研发的IPMS。到目前为止，在我的研究生研究中，我使用了化学蛋白质组学方法 发现共价作用的天然产物尼伯来特靶向半胱氨酸的底物识别结构域 E3泛素连接酶RNF114和尼波利特可被开发为PROTAC新E3连接酶招募子 申请。在我的提案的F99阶段，我计划全面描述宁波利特和其他药物的广泛用途 在我的提案的F99阶段，为PROTAC应用程序合成RNF114招聘人员。在我的K00阶段 提议，我计划开发新的异双功能IPM范例，即以Kinase为靶向的嵌合体 (KinaTACs)、磷酸酶靶向嵌合体(PhosphaTACs)、乙酰基转移酶靶向嵌合体(ATTACs)、 和脱乙酰酶靶向嵌合体(DATAC)，使用化学蛋白质组学启用的共价配体发现 平台，为癌症治疗开发新的治疗方式。

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.