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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. 2010
Italo Beria, and
Dario Ballinari, and
Jay Aaron Bertrand, and
Daniela Borghi, and
Roberto Tiberio Bossi, and
Maria Gabriella Brasca, and
Paolo Cappella, and
Michele Caruso, and
Walter Ceccarelli, and
Antonella Ciavolella, and
Cinzia Cristiani, and
Valter Croci, and
Anna De Ponti, and
Gabriele Fachin, and
Ronald Dale Ferguson, and
Jacqueline Lansen, and
Jurgen Karl Moll, and
Enrico Pesenti, and
Helena Posteri, and
Rita Perego, and
Maurizio Rocchetti, and
Paola Storici, and
Daniele Volpi, and
Barbara Valsasina
Nerviano Medical Sciences Srl, Oncology, Viale Pasteur 10, 20014 Nerviano, (Mi), Italy. italo.beria@nervianoms.com
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 (IC(50) = 0.007 microM) as well as its crystal structure in complex with the methylated Plk1(36-345) construct. Compound 49 was active in cell proliferation against different tumor cell lines with IC(50) 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.
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