文章：

靶向泛素连接酶以稳定肿瘤抑制蛋白的治疗策略展望

A Perspective on Therapeutic Targeting Against Ubiquitin Ligases to Stabilize Tumor Suppressor Proteins

原文发布日期：13 February 2025

DOI: 10.3390/cancers17040626

类型: Article

开放获取: 是

英文摘要：

The loss of functions of tumor suppressor (TS) genes plays a key role in not only tumor initiation but also tumor progression leading to poor prognosis. While therapeutic inhibition of oncogene-encoded kinases has shown clinical success, restoring TS functions remains challenging due to conceptual and technical limitations. E3 ubiquitin ligases that ubiquitinate TS proteins for accelerated degradation in cancers emerge as promising therapeutic targets. Unlike proteasomal inhibitors with a broad spectrum, inhibitors of an E3 ligase would offer superior selectivity and efficacy in enhancing expression of its substrate TS proteins as far as the TS proteins retain wild-type structures. Recent advances in developing E3 inhibitors, including MDM2 inhibitors, highlight their potential and ultimately guide the framework to establish E3 inhibition as effective strategies to treat specific types of cancers. This review explores E3 ligases that negatively regulate bona fide TS proteins, the developmental status of E3 inhibitors, and their promise and pitfalls as therapeutic agents for anti-cancer precision medicine.

摘要翻译： 

肿瘤抑制基因（TS）功能的丧失不仅在肿瘤发生中起关键作用，还导致肿瘤进展及不良预后。尽管针对癌基因编码激酶的治疗性抑制已取得临床成功，但由于概念和技术限制，恢复TS功能仍具挑战性。在癌症中通过泛素化促进TS蛋白加速降解的E3泛素连接酶，已成为有前景的治疗靶点。与广谱的蛋白酶体抑制剂不同，只要TS蛋白保持野生型结构，针对特定E3连接酶的抑制剂在增强其底物TS蛋白表达方面将提供更优的选择性和疗效。E3抑制剂（包括MDM2抑制剂）研发的最新进展凸显了其潜力，并为建立E3抑制作为治疗特定癌症类型的有效策略提供了框架。本综述探讨了负调控经典TS蛋白的E3连接酶、E3抑制剂的发展现状，及其作为抗癌精准医疗治疗药物的前景与局限。

原文链接：

A Perspective on Therapeutic Targeting Against Ubiquitin Ligases to Stabilize Tumor Suppressor Proteins