Abstract
This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Benzazepines / chemical synthesis*
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Benzazepines / pharmacokinetics
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Benzazepines / pharmacology
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Biological Availability
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Line, Tumor
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Cell Survival / drug effects
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Crystallography, X-Ray
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Drug Screening Assays, Antitumor
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Humans
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Lactams / chemical synthesis*
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Lactams / pharmacokinetics
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Lactams / pharmacology
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Mice
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Mice, Nude
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Mitosis
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Models, Molecular
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Neoplasm Transplantation
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Polo-Like Kinase 1
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Protein Conformation
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Thiones / chemical synthesis*
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Thiones / pharmacokinetics
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Thiones / pharmacology
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Transplantation, Heterologous
Substances
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9-trifluoromethyl-2-((5-(3-(dimethylamino)propyl)-2-methylpyridin-3-yl)amino)-5,7-dihydro-6H-pyrimido(5,4-d)(1)benzazepine-6-thione
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Antineoplastic Agents
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Benzazepines
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Cell Cycle Proteins
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Lactams
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Proto-Oncogene Proteins
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Thiones
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Protein Serine-Threonine Kinases