抗肿瘤Polo样激酶1抑制剂的研究进展

Advances on the study of PLK1 inhibitors as antitumor agents

Polo样激酶1(PLK1)是一种结构和功能高度保守的丝氨酸/苏氨酸蛋白激酶,在细胞有丝分裂阶段发挥重要的作用。在人类80%的肿瘤类型中,PLK1过度表达,而在正常组织中,该激酶很少表达。临床治疗中,该激酶的过度表达是多种肿瘤不良预后的标志之一。PLK1抑制剂可以对细胞有丝分裂的多个阶段产生作用,如阻碍中心体成熟、纺锤体形成和胞质分裂等,从而诱导分裂混乱、扰乱周期进程并最终导致肿瘤细胞死亡。因此,对PLK1的研究是抗肿瘤药物开发中的热点之一。本文综述了不同化学结构类型的PLK1抑制剂的临床前研究及若干化合物的临床研究进展。

Polo-like kinases 1 is a highly conserved serine/threonine protein kinase that plays a key role in regulation of mitosis.In about 80% of human tumors,of various origins,PLK1 is over expressed;while,PLK1 mRNA is often absent in the normal tissues.Meanwhile,over-expression of PLK1 is associated with a poor prognosis in several tumor types and a lower overall survival rate.PLK1 inhibitors can interfere with different stages of mitosis,such as centrosome maturation,spindle formation,chromosome separation,and cytokinesis,inducing mitotic chaos and severe perturbance of cell cycle progression,which eventually lead to tumor cell death.Therefore,PLK1 is one of the most attractive and promising targets for antitumor drug development.This review introduces PLK1 inhibitors of different structures in preclinical or clinical development.