靶向蛋白质降解 (TPD) 已成为一种创新的治疗策略，通过利用细胞泛素蛋白酶体系统 (UPS)（涉及 600 多种 E3 泛素连接酶）选择性降解特定蛋白质。最近的蛋白质组分析报告了人类肿瘤特异性 E3 连接酶。这些肿瘤特异性 E3 连接酶配体的开发将为肿瘤特异性 TPD 提供有效的癌症治疗解决方案。这篇综述提供了公共数据库中仅在特定类型肿瘤中发现的 E3 连接酶的完整列表，并重点介绍了通过基于片段的方法。它详细介绍了它们的发现过程以及精确 TPD 和有效癌症治疗的潜在应用。当前使用蛋白水解靶向嵌合体 (PROTAC) 的 TPD 策略主要利用通用 E3 连接酶，例如 CRBN 和 VHL。由于这些 E3 连接酶在大多数人类细胞类型中表现出有效的蛋白质降解活性，因此基于 CRBN 和 VHL 的 PROTAC 可能会在脱靶组织中表现出不良的 TPD，这通常会导致副作用。因此，开发肿瘤特异性 E3 连接酶配体对于有效的癌症治疗至关重要。基于片段的配体发现 (FBLD) 方法将加速这些肿瘤特异性 E3 连接酶配体和相关 PROTAC 的识别，从而推动靶向癌症治疗领域的发展。

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.