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. Epub 2011 Mar 21.

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.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Proliferation / drug effects
  • Clinical Trials, Phase I as Topic
  • Inhibitory Concentration 50
  • Mice
  • Mice, Nude
  • Molecular Structure
  • Neoplasms / drug therapy
  • Polo-Like Kinase 1
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • NMS P937
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pyrazoles
  • Quinazolines
  • Protein Serine-Threonine Kinases