靶向阻断蛋白-蛋白相互作用的抗肿瘤药研发

Development of Antineoplastics Targeting Blocking Protein-protein Interactions

蛋白-蛋白相互作用(PPI)以及通过相互作用而形成的蛋白复合物是细胞完成各项基本功能的重要基础。大多数重要的生命活动,如DNA的复制与转录、蛋白质的合成与转运、细胞信号转导与物质代谢调节等,都是通过密集的PPI网络维持的。基因突变、表观遗传学改变、细胞微环境变化能够干扰PPI模式或者直接诱导蛋白结合,形成新的、肿瘤特有的相互作用,导致肿瘤的发生、发展、侵袭以及转移。近年来,以PPI为靶点进行的抗肿瘤药研发取得了显著进展,有些药物正处于临床试验阶段或已获得批准上市。越来越多的证据表明,靶向特异性PPI的药物可能比抑制原癌基因蛋白活性的药物具有更高的特异性和疗效,为治愈特定肿瘤提供了治疗机遇。该综述系统总结了靶向PPI的抗肿瘤药研究进展,阐述其研发所面临的挑战及对策,以期为靶向PPI的抗肿瘤药研发提供参考。

Protein-protein interactions(PPIs)and the protein complexes formed through the interactions are essential for the cells to perform various basic functions.Most important life activities,such as DNA replication and transcription,protein synthesis and transport,cellular signal transduction and regulation of substance metabolism,are maintained through dense PPI networks.Genetic mutations,epigenetic alterations,and changes in the cellular microenvironment can interfere with PPI patterns or directly induce protein binding to form new tumor-specific interactions,leading to the genesis,progression,invasion and metastasis of tumors.In recent years,significant progress has been made in developing antineoplastics targeting PPI,some of which are in clinical trials or have been approved for marketing.There is growing evidence that drugs targeting specific PPI may have higher specificity and efficacy than those that inhibit the activity of proto-oncogene proteins and offer therapeutic opportunities to cure specific cancers.This paper systematically reviews the research progress of antineoplastics targeting PPI,and describes the challenges and countermeasures for the research of antineoplastics targeting PPI to provide a reference for their development.