靶向热休克蛋白90的双功能小分子抑制剂的抗肿瘤研究进展

Advances in antitumor research of bifunctional small molecule inhibitors targeting heat shock protein 90

热休克蛋白90(heat shock protein 90,Hsp90)家族是一组高度保守的分子,在维持细胞稳态中发挥重要作用。Hsp90及其共同伴侣可调控多种途径和细胞功能,如细胞生长、细胞周期控制和细胞凋亡等。Hsp90与肿瘤等疾病的发生发展密切相关,是癌症治疗的一个有吸引力的靶点。抑制Hsp90表达可同时影响多种致癌途径。Hsp90小分子抑制剂由于其低疗效、毒性或耐药性等问题,大多数抑制剂都处于临床试验阶段,但其与组蛋白去乙酰化酶(histone deacetylase,HDAC)抑制剂、微管蛋白抑制剂、拓扑异构酶II(topoisomerase II,Topo II)抑制剂等联合使用时,具有明显的协同抗肿瘤作用。针对这一问题,设计Hsp90双靶点抑制剂以提高疗效和降低耐药性是一种有效的肿瘤治疗策略。本文简要介绍了Hsp90的结构域及其生物学功能,并讨论了Hsp90双重抑制剂的设计、发现和构效关系,旨在从药物化学的角度为新型Hsp90双重抑制剂的发现和临床药物研究提供参考。

The heat shock protein 90(Hsp90)protein family is a cluster of highly conserved molecules that play an important role in maintaining cellular homeostasis.Hsp90 and its co-chaperones regulate a variety of pathways and cellular functions,such as cell growth,cell cycle control and apoptosis.Hsp90 is closely associated with the occurrence and development of tumors and other diseases,making it an attractive target for cancer therapeutics.Inhibition of Hsp90 expression can affect multiple oncogenic pathways simultaneously.Most Hsp90 small molecule inhibitors are in clinical trials due to their low efficacy,toxicity or drug resistance,but they have obvious synergistic anti-tumor effect when used with histone deacetylase(HDAC)inhibitors,tubulin inhibitors or topoisomerase II(Topo II)inhibitors.To address this issue,the design of Hsp90 dual-target inhibitors can improve efficacy and reduce drug resistance,making it an effective tumor treatment strategy.In this paper,the domain and biological function of Hsp90 are briefly introduced,and the design,discovery and structure-activity relationship of Hsp90 dual inhibitors are discussed,in order to provide reference for the discovery of novel Hsp90 dual inhibitors and clinical drug research from the perspective of medicinal chemistry.