蛋白水解靶向嵌合体技术在恶性肿瘤治疗中的研究进展

Research progress on proteolysis-targeting chimera (PROTAC) technology in the treatment of malignant tumors

摘要:

传统的癌症治疗方式主要包括手术、放疗和化疗。近年来，随着对癌症发病机制的深入了解，免疫及靶向治疗也成为癌症治疗的重要临床策略。放疗和化疗对正常细胞的毒副作用较大，免疫及靶向治疗易产生耐药性从而降低疗效。为解决这一难题，靶向特定的致病蛋白成为人们研究的热点。蛋白水解靶向嵌合体（PROTAC）的出现为癌症的治疗带来了希望，其是一类消除靶蛋白的新型药物，通过泛素-蛋白酶体系统诱导目的蛋白泛素化降解，与小分子抑制剂相比，其还能特异性降解致病目标蛋白，同时在降低药物毒性和不良反应、克服耐药性及靶向“不可成药”靶点等方面具有独特优势。该文综述PROTAC技术在恶性肿瘤中的研究进展，评估其在治疗中的优劣势，为癌症治疗提供参考。

Abstract:

Traditional cancer treatment modalities primarily include surgery, radiotherapy, and chemotherapy. In recent years, with an in-depth understanding of cancer pathogenesis, immunotherapy and targeted therapy have also emerged as pivotal clinical strategies for cancer management. However, radiotherapy and chemotherapy exhibit substantial toxic side effects on normal cells, while immunotherapy and targeted therapies are prone to drug resistance, thereby diminishing therapeutic efficacy. To address these challenges, targeting specific pathogenic proteins has become a focal area of research. The advent of proteolysis-targeting chimeras (PROTACs) has introduced a promising therapeutic avenue for cancer treatment. PROTACs represent a novel class of agents designed to eliminate target proteins by hijacking the ubiquitin-proteasome system (UPS) to induce ubiquitination and degradation of the target protein. Compared to small-molecule inhibitors, PROTACs not only specifically degrade pathogenic target proteins but also demonstrate unique advantages in reducing drug toxicity and adverse effects, overcoming drug resistance, and targeting "undruggable" oncogenic proteins. This review summarizes recent advancements in PROTAC technology for malignant tumors, evaluates its strengths and limitations in therapeutic applications, and provides insights to inform future research in cancer therapy.