Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo[3,2-d]pyrimidine scaffold

J Med Chem. 2011 Dec 8;54(23):8030-50. doi: 10.1021/jm2008634. Epub 2011 Nov 4.


Dual inhibitors of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors' ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Biological Availability
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / antagonists & inhibitors*
  • Female
  • Humans
  • Hydroxybutyrates / chemical synthesis*
  • Hydroxybutyrates / pharmacokinetics
  • Hydroxybutyrates / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Neoplasm Transplantation
  • Protein Conformation
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology
  • Pyrroles / chemical synthesis*
  • Pyrroles / pharmacokinetics
  • Pyrroles / pharmacology
  • Rats
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Transplantation, Heterologous


  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Hydroxybutyrates
  • Pyrimidines
  • Pyrroles
  • N-(2-(4-((3-chloro-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo(3,2-d)pyrimidin-5-yl)ethyl)-3-hydroxy-3-methylbutanamide
  • Adenosine Triphosphate
  • ERBB2 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2

Associated data

  • PDB/3RCD