Identification of Polo-Like Kinase 1 Inhibitors Using Structure-Based Molecular Design

摘要

Polo-like kinase 1 (PLK1), a mitotic cyclin-independent serine-threonine kinase, is a member of the family of pololike kinases, which are involved in a wide variety of cell evele processes. Polo-like kinases were first identified in Drophila melanogaster, where mutations of the kinase lead to abnormal mitotic and meiotic divisions caused by failure of a properly formed mitotic spindle. The human PLK family includes five closely related members, PLK1, PLK2, PLK3, PLK4, and PLK5. Overexpression of the PLK1 gene has been found in multiple cancers in humans: glioma, breast cancer, cervical carcinoma, and non-small-cell lung cancer. Inhibition of PLK1 by small-molecule inhibitors of its catalytic activity is currently being explored as a treatment for cancer. BI-2536 has been shown to inhibit PLK. isoforms in vitro with low nanomolar potency and with high selectivity against a large panel of kinases. BI-2536 potently inhibits the proliferation of a wide variety of human cancer cell lines and causes regression of tumor xenografts in mice; it is currently undergoing clinical trials.