Abstract
Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase considered to be the master player of cell-cycle regulation during mitosis. It is indeed involved in centrosome maturation, bipolar spindle formation, chromosome separation, and cytokinesis. PLK1 is overexpressed in a variety of human tumors and its overexpression often correlates with poor prognosis. Although five different PLKs are described in humans, depletion or inhibition of kinase activity of PLK1 is sufficient to induce cell-cycle arrest and apoptosis in cancer cell lines and in xenograft tumor models. NMS-P937 is a novel, orally available PLK1-specific inhibitor. The compound shows high potency in proliferation assays having low nanomolar activity on a large number of cell lines, both from solid and hematologic tumors. NMS-P937 potently causes a mitotic cell-cycle arrest followed by apoptosis in cancer cell lines and inhibits xenograft tumor growth with clear PLK1-related mechanism of action at well-tolerated doses in mice after oral administration. In addition, NMS-P937 shows potential for combination in clinical settings with approved cytotoxic drugs, causing tumor regression in HT29 human colon adenocarcinoma xenografts upon combination with irinotecan and prolonged survival of animals in a disseminated model of acute myelogenous leukemia in combination with cytarabine. NMS-P937, with its favorable pharmacologic parameters, good oral bioavailability in rodent and nonrodent species, and proven antitumor activity in different preclinical models using a variety of dosing regimens, potentially provides a high degree of flexibility in dosing schedules and warrants investigation in clinical settings.
Highlights
Mitotic cell-cycle progression is tightly regulated through reversible covalent protein phosphorylation events coordinated by regulatory kinases, including members of the polo subfamily [1]
Is frequently found to be overexpressed in numerous tumor types including pancreatic [3], colon [4], prostate [5], ovary [6], breast [7], head and neck [8], anaplastic thyroid [9] carcinomas, melanoma [10], and in a set of hematologic malignancies comprising acute myelogenous leukemia (AML; refs. 11, 12), and non-Hodgkins lymphoma [13], with overexpression often correlated with poor prognosis
NMS-P937 is highly selective for Polo-like kinase 1 (PLK1) when tested on a panel of 63 protein kinases representative of the human kinome superfamily
Summary
Mitotic cell-cycle progression is tightly regulated through reversible covalent protein phosphorylation events coordinated by regulatory kinases, including members of the polo subfamily [1]. Interference with PLK1 activity and/or function by a variety of methods including antisense oligonucleotides [14], short interfering RNA [15], and proteins encoding dominant-negative PLK1 [16] results in tumor cell apoptosis in culture and in vivo. Normal cells have been described to better tolerate PLK1 depletion as compared with tumor cells [17]. These data support PLK1 as a potentially valuable target for anticancer drug development. A PLK1 selective inhibitor might be expected to have a superior safety profile compared with pan-PLK inhibitors
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