Novel inhibitors of epidermal growth factor receptor: (4-(Arylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(1H-indol-2-yl)methanones and (1H-indol-2-yl)(4-(phenylamino)thieno[2,3-d]pyrimidin-6-yl)methanones

Bioorg Med Chem. 2012 Jan 1;20(1):125-36. doi: 10.1016/j.bmc.2011.11.023. Epub 2011 Nov 20.

Abstract

Several members of the quinazoline class of known tyrosine kinase inhibitors are approved anticancer agents, often showing selectivity for receptors of the HER/ErbB-family. Combining structural elements of this class with the bisindolylmethanone-structure led to a series of novel compounds. These compounds inhibited EGFR in the nanomolar range. Moreover, inhibition of EGFR autophosphorylation in intact A431 cells was shown, with IC(50) values ranging form 0.3-1μM for compound 42, and 0.1-0.3μM for 45. In a panel of 42 human tumor cell lines the sensitivity profile of the novel compounds was shown to be similar to that of the quinazoline class of tyrosine kinase inhibitors lapatinib and erlotinib (Tarceva®).

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry*
  • Indoles / pharmacology
  • Phosphorylation / drug effects
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacology
  • Structure-Activity Relationship

Substances

  • (4-(3-chloro-4-fluorophenylamino)thieno(2,3-d)pyrimidin-6-yl)(5-hydroxy-1H-indol-2-yl)methanone
  • (4-(3-chlorophenylamino)thieno(2,3-d)pyrimidin-6-yl)(1H-indol-2-yl)methanone
  • Antineoplastic Agents
  • Indoles
  • Pyrimidines
  • Quinazolines
  • ErbB Receptors
  • pyrimidine