American Chemical Society
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Identification of 4,5-Dihydro-1H-pyrazolo[4,3-h]quinazoline Derivatives as a New Class of Orally and Selective Polo-Like Kinase 1 Inhibitors

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journal contribution
posted on 2010-05-13, 00:00 authored by Italo Beria, Dario Ballinari, Jay Aaron Bertrand, Daniela Borghi, Roberto Tiberio Bossi, Maria Gabriella Brasca, Paolo Cappella, Michele Caruso, Walter Ceccarelli, Antonella Ciavolella, Cinzia Cristiani, Valter Croci, Anna De Ponti, Gabriele Fachin, Ronald Dale Ferguson, Jacqueline Lansen, Jurgen Karl Moll, Enrico Pesenti, Helena Posteri, Rita Perego, Maurizio Rocchetti, Paola Storici, Daniele Volpi, Barbara Valsasina
Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression whose overexpression is often associated with oncogenesis and therefore is recognized as an attractive therapeutic target in the treatment of proliferative diseases. Here we discuss the structure−activity relationship of the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline class of compounds that emerged from a high throughput screening (HTS) campaign as potent inhibitors of Plk1 kinase. Furthermore, we describe the discovery of 49, 8-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, as a highly potent and specific ATP mimetic inhibitor of Plk1 (IC50 = 0.007 μM) as well as its crystal structure in complex with the methylated Plk136−345 construct. Compound 49 was active in cell proliferation against different tumor cell lines with IC50 values in the submicromolar range and active in vivo in the HCT116 xenograft model where it showed 82% tumor growth inhibition after repeated oral administration.