Discovery of a novel Her-1/Her-2 dual tyrosine kinase inhibitor for the treatment of Her-1 selective inhibitor-resistant non-small cell lung cancer

J Med Chem. 2009 Nov 12;52(21):6880-8. doi: 10.1021/jm901146p.

Abstract

A novel series of (S)-1-acryloyl-N-[4-(arylamino)-7-(alkoxy)quinazolin-6-yl]pyrrolidine-2-carboxamides were synthesized and evaluated as Her-1/Her-2 dual inhibitors. In contrast to the Her-1 selective inhibitors, our novel compounds are irreversible inhibitors of Her-1 and Her-2 tyrosine kinases with the potential to overcome clinically relevant, mutation-induced drug resistance. The selected compounds (19c, 19d) showed excellent EGFR inhibition activity even toward the T790M mutation of Her-1 tyrosine kinase with excellent selectivity. The excellent pharmacokinetic profiles of these compounds in rats and their robust in vivo efficacy in an A431 xenograft model clearly demonstrate that they merit further investigation as novel therapeutic agents for EGFR-targeting treatment of solid tumors, especially Her-1 selective inhibitor-resistant non-small cell lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / chemical synthesis*
  • Aniline Compounds / pharmacokinetics
  • Aniline Compounds / pharmacology
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • Erlotinib Hydrochloride
  • Female
  • Gefitinib
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Male
  • Mice
  • Mice, Nude
  • Molecular Conformation
  • Neoplasm Transplantation
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / pharmacokinetics
  • Pyrrolidines / pharmacology
  • Quinazolines / chemical synthesis*
  • Quinazolines / pharmacokinetics
  • Quinazolines / pharmacology
  • Rats
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Transplantation, Heterologous

Substances

  • 1-acryloyl-N-(4-(3-chloro-2,4-difluorophenylamino)-7-(2-methoxyethoxy)quinazolin-6-yl)pyrrolidine-2-carboxamide
  • 1-acryloyl-N-(4-(3-chloro-2-fluorophenylamino)-7-(2-methoxyethoxy)quinazolin-6-yl)pyrrolidine-2-carboxamide
  • Aniline Compounds
  • Antineoplastic Agents
  • Pyrrolidines
  • Quinazolines
  • Erlotinib Hydrochloride
  • ErbB Receptors
  • Receptor, ErbB-2
  • Gefitinib