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

Italo Beria (Lead / Corresponding author), 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

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85 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2969-2974
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number10
Early online date21 Mar 2011
DOIs
Publication statusPublished - 15 May 2011

Keywords

  • In vivo activity
  • Kinase inhibitor
  • Phase I clinical trials
  • PLK1
  • Polo-like kinase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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