Recent updates on third generation EGFR inhibitors and emergence of fourth generation EGFR inhibitors to combat C797S resistance

Eur J Med Chem. 2017 Dec 15:142:32-47. doi: 10.1016/j.ejmech.2017.05.027. Epub 2017 May 11.

Abstract

EGFR T790M mutation leads to resistance to most of clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation have been in active clinical development, which includes osimertinib, rociletinib, HM61713, ASP8273, EGF816, and PF-06747775. On the other hand recently EGFR C797S mutation was reported to be a leading mechanism of resistance to the third-generation inhibitors. The C797S mutation appears to be an ideal target for overcoming the acquired resistance to the third generation inhibitors. This review summarizes the third generation inhibitors, synthesis, their mechanism of resistance and latest development on the discovery of a fourth-generation EGFR TKIs and U to Y allosteric strategies to combat the C797S EGFR resistance problem.

Keywords: C797S EGFR; Fourth generation EGFR inhibitors; Non-small cell lung cancer; T790M EGFR.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Drug Discovery
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics*
  • Humans
  • Lung / drug effects
  • Lung / metabolism
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Models, Molecular
  • Point Mutation*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • EGFR protein, human
  • ErbB Receptors