4,5-Dihydro-1H-pyrazolo[4,3-h]quinazolines as potent and selective Polo-like kinase 1 (PLK1) inhibitors

A series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives was optimized as Polo-like kinase 1 inhibitors. Extensive SAR afforded a highly potent and selective PLK1 compound. The compound showed good antiproliferative activity when tested in a panel of tumor cell lines with PLK1 related mechanism of action and with good in vivo antitumor efficacy in two xenograft models after iv administration.

Graphical abstractA 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline series of Polo-like kinase inhibitors is reported and the SAR disclosed. The series led to low nanomolar PLK1 inhibitors. Compound 4 was tested in vivo showing good antitumor efficacy after iv administration.Figure optionsDownload full-size imageDownload as PowerPoint slide