Research Articles: Therapeutics, Targets, and Development

In vitro biological activity of a novel small-molecule inhibitor of polo-like kinase 1

^{1 1}Oncology Biology, ²Assay Development, ³Oncology Chemistry, ⁴Translational Medicine and Genetics, GlaxoSmithKline, Research Triangle Park, North Carolina; ⁵Clinical Research Department 8 Vaccine, GlaxoSmithKline K.K., Shibuya, Tokyo, Japan; and ⁶Molecular Biology Unit, Department of Biosciences, Tsukuba Research Laboratories, GlaxoSmithKline K.K., Tsukuba, Ibaraki, Japan

^* To whom correspondence should be addressed. E-mail: timothy.j.lansing{at}gsk.com.

	Abstract

Polo-like kinase 1 (PLK1) plays key roles in the regulation of mitotic progression, including mitotic entry, spindle formation, chromosome segregation, and cytokinesis. PLK1 expression and activity are strongly linked to proliferating cells. Many studies have shown that PLK1 expression is elevated in a variety of tumors, and high expression often correlates with poor prognosis. Using a variety of methods, including small-molecule inhibition of PLK1 function and/or activity, apoptosis in cancer cell lines, cell cycle arrest in normal cell lines, and antitumor activity in vivo have been observed. In the present study, we have examined the in vitro biological activity of a novel and selective thiophene benzimidazole ATP-competitive inhibitor of PLK1 and PLK3 (5-(5,6-dimethoxy-1H-benzimidazol-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxamide, called compound 1). Compound 1 has low nanomolar activity against the PLK1 and PLK3 enzymes and potently inhibits the proliferation of a wide variety of tumor cell lines. In the lung adenocarcinoma cell line NCI-H460, compound 1 induces a transient G₂-M arrest, mitotic spindle defects, and a multinucleate phenotype resulting in apoptosis, whereas normal human diploid fibroblasts arrest in G₂-M and show little apoptosis. We also describe a cellular mechanistic assay that was developed to identify potent intracellular inhibitors of PLK1. In addition to its potential as a therapeutic agent for treating cancer, compound 1 is also a useful tool molecule for further investigation of the biological functions of PLK1 and PLK3. [Mol Cancer Ther 2007;6(2):OF1-10]

Key Words: Polo-like kinase 1, kinase inhibitor, mechanistic assay, mitotic inhibitor, mitosis

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