As a widely considerable target in chemical biology and pharmacological research, rat sarcoma (RAS) gene mutations play a critical driving factor in several fatal cancers. Despite the great progress of RAS subtype-specific inhibitors, rapid acquired drug resistance could limit their further clinical applications. Proteolysis targeting chimera (PROTAC) has emerged as a powerful tool to handle “undruggable” targets and exhibited significant therapeutic benefit for the combat of drug resistance. Owing to unique molecular mechanism and binding kinetics, PROTAC is expected to become a feasible strategy to break the bottleneck of classical RAS inhibitors. This review aims to discuss the current advances of RAS inhibitors and especially focus on PROTAC strategy targeting RAS mutations and their downstream effectors for relevant cancer treatment.

中文翻译：

---

RAS靶向治疗策略进展：从小分子抑制剂到靶向嵌合体的蛋白水解

作为化学生物学和药理学研究中广泛关注的目标，大鼠肉瘤（RAS）基因突变在几种致命癌症中发挥着关键的驱动因素。尽管RAS亚型特异性抑制剂取得了巨大进展，但快速获得的耐药性可能限制其进一步的临床应用。蛋白水解靶向嵌合体（PROTAC）已成为处理“不可成药”靶标的强大工具，并在对抗耐药性方面表现出显着的治疗益处。由于独特的分子机制和结合动力学，PROTAC有望成为突破经典RAS抑制剂瓶颈的可行策略。本综述旨在讨论RAS抑制剂的最新进展，特别关注针对RAS突变及其下游效应子用于相关癌症治疗的PROTAC策略。