Novel C-5 aminomethyl pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases

Bioorg Med Chem Lett. 2007 May 15;17(10):2828-33. doi: 10.1016/j.bmcl.2007.02.050. Epub 2007 Feb 27.

Abstract

Novel C-5 aminomethyl pyrrolotriazines were prepared and optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The homopiperazine, 1p, emerged as a key lead and it showed promising oral efficacy in EGFR and dual EGFR/HER2 driven human tumor xenograft models. It is hypothesized that the C-5 homopiperazine side chain binds in the ribose-phosphate portion of the ATP binding pocket.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / antagonists & inhibitors*
  • Humans
  • Methylamines / chemistry
  • Methylamines / pharmacology*
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Neoplasm Transplantation
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Triazines / chemistry
  • Triazines / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Methylamines
  • Pyrroles
  • Triazines
  • aminomethyl pyrrolotriazine
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Receptor, ErbB-2