1034615-33-2Relevant articles and documents
Identification of 4,5-dihydro-1 H -pyrazolo[4,3- h ]quinazoline Derivatives as a new class of orally and selective polo-like kinase 1 inhibitors
Beria, Italo,Ballinari, Dario,Bertrand, Jay Aaron,Borghi, Daniela,Bossi, Roberto Tiberio,Brasca, Maria Gabriella,Cappella, Paolo,Caruso, Michele,Ceccarelli, Walter,Ciavolella, Antonella,Cristiani, Cinzia,Croci, Valter,De Ponti, Anna,Fachin, Gabriele,Ferguson, Ronald Dale,Lansen, Jacqueline,Moll, Jurgen Karl,Pesenti, Enrico,Posteri, Helena,Perego, Rita,Rocchetti, Maurizio,Storici, Paola,Volpi, Daniele,Valsasina, Barbara
experimental part, p. 3532 - 3551 (2010/09/11)
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 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.
