Discovery of pyrrolopyrimidine inhibitors of Akt

Bioorg Med Chem Lett. 2010 Oct 1;20(19):5607-12. doi: 10.1016/j.bmcl.2010.08.053. Epub 2010 Aug 13.

Abstract

The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor xenografts.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Binding Sites
  • Cell Line
  • Crystallography, X-Ray
  • Drug Design
  • Drug Evaluation, Preclinical
  • High-Throughput Screening Assays
  • Humans
  • Mice
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry*
  • Pyrroles / pharmacology
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • AKT1S1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Phosphoproteins
  • Protein Isoforms
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • pyrrolopyrimidine
  • Proto-Oncogene Proteins c-akt