NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor

As part of our drug discovery effort, we identified and developed 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as PLK1 inhibitors. We now report the optimization of this class that led to the identification of NMS-P937, a potent, selective and orally available PLK1 inhibitor. Also, in order...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-05, Vol.21 (10), p.2969-2974
Hauptverfasser:	Beria, Italo, Bossi, Roberto T, Brasca, Maria Gabriella, Caruso, Michele, Ceccarelli, Walter, Fachin, Gabriele, Fasolini, Marina, Forte, Barbara, Fiorentini, Francesco, Pesenti, Enrico, Pezzetta, Daniele, Posteri, Helena, Scolaro, Alessandra, Depaolini, Stefania Re, Valsasina, Barbara
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Biological and medical sciences Cell Cycle Proteins - antagonists & inhibitors Cell Proliferation - drug effects clinical trials Clinical Trials, Phase I as Topic crystal structure drugs General aspects Inhibitory Concentration 50 Medical sciences Mice Mice, Nude Miscellaneous Molecular Structure Neoplasms - drug therapy oral administration Pharmacology. Drug treatments Polo-Like Kinase 1 Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Protein Serine-Threonine Kinases - antagonists & inhibitors Proto-Oncogene Proteins - antagonists & inhibitors Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacology Quinazolines - chemical synthesis Quinazolines - chemistry Quinazolines - pharmacology Structure-Activity Relationship Xenograft Model Antitumor Assays
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Zusammenfassung:	As part of our drug discovery effort, we identified and developed 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as PLK1 inhibitors. We now report the optimization of this class that led to the identification of NMS-P937, a potent, selective and orally available PLK1 inhibitor. Also, in order to understand the source of PLK1 selectivity, we determined the crystal structure of PLK1 with NMS-P937. The compound was active in vivo in HCT116 xenograft model after oral administration and is presently in Phase I clinical trials evaluation.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.03.054