1. NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor.
- Author
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Beria I, Bossi RT, Brasca MG, Caruso M, Ceccarelli W, Fachin G, Fasolini M, Forte B, Fiorentini F, Pesenti E, Pezzetta D, Posteri H, Scolaro A, Re Depaolini S, and Valsasina B
- Subjects
- Administration, Oral, Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Clinical Trials, Phase I as Topic, Inhibitory Concentration 50, Mice, Mice, Nude, Molecular Structure, Neoplasms drug therapy, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Pyrazoles chemical synthesis, Pyrazoles chemistry, Quinazolines chemical synthesis, Quinazolines chemistry, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Polo-Like Kinase 1, Antineoplastic Agents pharmacology, Cell Cycle Proteins antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Proto-Oncogene Proteins antagonists & inhibitors, Pyrazoles pharmacology, Quinazolines pharmacology
- Abstract
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., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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