Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors

Bioorg Med Chem Lett. 2017 Mar 1;27(5):1311-1315. doi: 10.1016/j.bmcl.2016.10.009. Epub 2016 Oct 15.

Abstract

Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.

Keywords: Antitumor activity; Multidrug resistance; PLK1 inhibitor; Structure-based drug design.

MeSH terms

  • Animals
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Drug Design*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Female
  • HT29 Cells
  • Heterografts
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Mice
  • Molecular Structure
  • Polo-Like Kinase 1
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Pteridines / chemical synthesis*
  • Pteridines / chemistry
  • Pteridines / pharmacology
  • Structure-Activity Relationship

Substances

  • Cell Cycle Proteins
  • Enzyme Inhibitors
  • Imidazoles
  • Proto-Oncogene Proteins
  • Pteridines
  • imidazolone
  • Protein Serine-Threonine Kinases