NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor

  • Bioorg Med Chem Lett. 2011 May 15;21(10):2969-74. doi: 10.1016/j.bmcl.2011.03.054.
Italo Beria  1 ,  Roberto T Bossi ,  Maria Gabriella Brasca ,  Michele Caruso ,  Walter Ceccarelli ,  Gabriele Fachin ,  Marina Fasolini ,  Barbara Forte ,  Francesco Fiorentini ,  Enrico Pesenti ,  Daniele Pezzetta ,  Helena Posteri ,  Alessandra Scolaro ,  Stefania Re Depaolini ,  Barbara Valsasina
Affiliations
  • 1. Nerviano Medical Sciences srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano, MI, Italy. [email protected]
PMID: 21470862 DOI: 10.1016/j.bmcl.2011.03.054
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.

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