BI 2536, a Potent and Selective Inhibitor of Polo-like Kinase 1, Inhibits Tumor Growth In Vivo

Abstract

Fine-mapping of the cell-division cycle, notably the identification of mitotic kinase signaling pathways, provides novel opportunities for cancer-drug discovery. As a key regulator of multiple steps during mitotic progression across eukaryotic species, the serine/threonine-specific Polo-like kinase 1 (Plk1) is highly expressed in malignant cells and serves as a negative prognostic marker in specific human cancer types [1Barr F.A. Sillje H.H. Nigg E.A. Polo-like kinases and the orchestration of cell division.Nat. Rev. Mol. Cell Biol. 2004; 5: 429-440Crossref PubMed Scopus (847) Google Scholar, 2Takai N. Hamanaka R. Yoshimatsu J. Miyakawa I. Polo-like kinases (Plks) and cancer.Oncogene. 2005; 24: 287-291Crossref PubMed Scopus (319) Google Scholar, 3Strebhardt K. Ullrich A. Targeting polo-like kinase 1 for cancer therapy.Nat. Rev. Cancer. 2006; 6: 321-330Crossref PubMed Scopus (662) Google Scholar, 4van de Weerdt B.C. Medema R.H. Polo-like kinases: A team in control of the division.Cell Cycle. 2006; 5: 853-864Crossref PubMed Scopus (217) Google Scholar]. Here, we report the discovery of a potent small-molecule inhibitor of mammalian Plk1, BI 2536, which inhibits Plk1 enzyme activity at low nanomolar concentrations. The compound potently causes a mitotic arrest and induces apoptosis in human cancer cell lines of diverse tissue origin and oncogenome signature. BI 2536 inhibits growth of human tumor xenografts in nude mice and induces regression of large tumors with well-tolerated intravenous dose regimens. In treated tumors, cells arrest in prometaphase, accumulate phosphohistone H3, and contain aberrant mitotic spindles. This mitotic arrest is followed by a surge in apoptosis, detectable by immunohistochemistry and noninvasive optical and magnetic resonance imaging. For addressing the therapeutic potential of Plk1 inhibition, BI 2536 has progressed into clinical studies in patients with locally advanced or metastatic cancers.