基于片段的策略用于发现肿瘤特异性E3连接酶的配体
Fragment-based approaches to discover ligands for tumor-specific E3 ligases
DOI 原文链接
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影响因子:4.9
分区:医学2区 / 药学2区
发表日期:2024 Dec
作者:
Junhyeong Yim, Solbi Kim, Hyung Ho Lee, Jin Soo Chung, Jongmin Park
DOI:
10.1080/17460441.2024.2415310
摘要
靶向蛋白质降解（TPD）作为一种创新的治疗策略，通过利用细胞的泛素-蛋白酶体系统（UPS）选择性降解特定蛋白，包括超过600种E3泛素连接酶。近期的蛋白质组分析报道了人类中的肿瘤特异性E3连接酶。开发这些肿瘤特异性E3连接酶的配体，将为实现肿瘤特异性TPD提供解决方案，从而有效治疗癌症。本文提供了一个全面的肿瘤中特异性E3连接酶的列表，来源于公共数据库，并强调了通过片段基础方法（FBLD）发现的这些配体的实例。详细介绍了其发现过程及其在精准TPD和有效癌症治疗中的潜在应用。目前的TPD策略主要利用通用E3连接酶（如CRBN和VHL）的蛋白质降解作用。由于这些E3连接酶在大多数人类细胞中表现出有效的蛋白质降解活性，基于CRBN和VHL的PROTACs可能在非靶组织中引发不良的TPD反应，从而导致副作用。因此，开发肿瘤特异性E3连接酶配体对于实现有效的癌症治疗至关重要。片段基础配体发现（FBLD）方法有望加速这些肿瘤特异性E3连接酶配体及相关PROTACs的识别，推动靶向癌症治疗的发展。
Abstract
Targeted protein degradation (TPD) has emerged as an innovative therapeutic strategy through selective degradation of specific proteins by harnessing the cellular ubiquitin-proteasome system (UPS), which involves over 600 E3 ubiquitin ligases. Recent proteome profiling reported tumor-specific E3 ligases in human. Development of those tumor-specific E3 ligase ligands would provide a solution for tumor-specific TPD for effective cancer treatment.This review provides a comprehensive list of E3 ligases found only in specific types of tumor from public databases and highlights examples of their ligands discovered through fragment-based approaches. It details their discovery process and potential applications for precise TPD and effective cancer treatments.Current TPD strategies using proteolysis-targeting chimeras (PROTACs) primarily utilize general E3 ligases, such as CRBN and VHL. Since these E3 ligases demonstrate effective protein degradation activity in most human cell types, CRBN and VHL-based PROTACs can exhibit undesired TPD in off-target tissues, which often leads to the side effects. Therefore, developing tumor-specific E3 ligase ligands can be crucial for effective cancer treatments. Fragment-based ligand discovery (FBLD) approaches would accelerate the identification of these tumor-specific E3 ligase ligands and associated PROTACs, thereby advancing the field of targeted cancer therapies.