NMS-P937, an orally available, specific small-molecule polo-like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies

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 tu...

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Published in:	Molecular cancer therapeutics Vol. 11; no. 4; pp. 1006 - 1016
Main Authors:	Valsasina, Barbara, Beria, Italo, Alli, Cristina, Alzani, Rachele, Avanzi, Nilla, Ballinari, Dario, Cappella, Paolo, Caruso, Michele, Casolaro, Alessia, Ciavolella, Antonella, Cucchi, Ulisse, De Ponti, Anna, Felder, Eduard, Fiorentini, Francesco, Galvani, Arturo, Gianellini, Laura M, Giorgini, Maria L, Isacchi, Antonella, Lansen, Jaqueline, Pesenti, Enrico, Rizzi, Simona, Rocchetti, Maurizio, Sola, Francesco, Moll, Jürgen
Format:	Journal Article
Language:	English
Published:	United States 01-04-2012
Subjects:	Administration, Oral Animals Antineoplastic Agents - pharmacology Cell Cycle Proteins - antagonists & inhibitors Cell Line, Tumor Cell Proliferation - drug effects Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism Dogs Female Haplorhini HL-60 Cells Humans Leukemia - drug therapy Leukemia - genetics Leukemia - metabolism Leukemia - pathology Mice Mice, Nude Mice, SCID Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Ovarian Neoplasms - metabolism Polo-Like Kinase 1 Protein Kinase Inhibitors - pharmacology Protein Serine-Threonine Kinases - antagonists & inhibitors Proto-Oncogene Proteins - antagonists & inhibitors Pyrazoles - pharmacology Quinazolines - pharmacology Rats Xenograft Model Antitumor Assays
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1535-7163 1538-8514
DOI:	10.1158/1535-7163.MCT-11-0765