Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist

The article discusses unlabeled, investigational, or alternative use(s) of a product, device or technique: review of novel drugs from several manufacturers for a novel target (Polo). The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers. Polo-like kinases (PLKs) are a group of highly con-served serine/threonine protein kinases that play a key role in processes such as cell division and checkpoint regulation of mitosis. About 80 % of human tumors, of various origins, express high levels of PLK transcripts. However, PLK mRNA is mostly absent in surrounding healthy tissues. Overexpression of PLK is associated with a poor prognosis in several tumor types and a lower overall survival rate. The overexpression of PLKs in hu-man tumors, but not in healthy nondividing cells, makes them an attractive, selective target for cancer drug de-velopment. PLK inhibitors interfere with different stages of mitosis, such as centrosome maturation, spin-dle formation, chromosome separation, and cytokinesis. They induce mitotic chaos and severely perturb cell cy-cle progression, eventually leading to cancer cell death. Several PLK inhibitors are in development and are un-dergoing evaluations as potential cancer treatments. This review includes an overview of PLK inhibitors in early clinical development (i.e., BI 2536, BI 6727, GSK461364, ON 019190.Na, and HMN-214) and in ad-vanced preclinical development (i.e., ZK-thiazolidi-none, NMS-1, CYC-800, DAP-81, and LC-445). If proof of principle is confirmed in large studies, PLK inhibi-tors will offer a new targeted antitumor therapy for can-cer patients. The Oncologist 2009;14:000–00