EGFR inhibitors from cancer to inflammation: Discovery of 4-fluoro-N-(4-(3-(trifluoromethyl)phenoxy)pyrimidin-5-yl)benzamide as a novel anti-inflammatory EGFR inhibitor

Bioorg Chem. 2019 May:86:112-118. doi: 10.1016/j.bioorg.2019.01.017. Epub 2019 Jan 12.

Abstract

EGFR inhibitors are well-known as anticancer agents. Quite differently, we report our effort to develop EGFR inhibitors as anti-inflammatory agents. Pyrimidinamide EGFR inhibitors eliciting low micromolar IC50 and the structurally close non-EGFR inhibitor urea analog were synthesized. Comparing their nitric oxide (NO) production inhibitory activity in peritoneal macrophages and RAW 246.7 macrophages indicated that their anti-inflammatory activity in peritoneal macrophages might be a sequence of EGFR inhibition. Further evaluations proved that compound 4d significantly and dose-dependently inhibits LPS-induced iNOS expression and IL-1β, IL-6, and TNF-α production via NF-κB inactivation in peritoneal macrophages. Compound 4d might serve as a lead compound for development of a novel class of anti-inflammatory EGFR inhibitors.

Keywords: Anti-inflammatory; Cytokines production; EGFR inhibitors; Macrophages; Nitric oxide production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Benzamides / chemical synthesis
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Cell Survival / drug effects
  • Cytokines / antagonists & inhibitors
  • Cytokines / biosynthesis
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Molecular Structure
  • Nitric Oxide / antagonists & inhibitors
  • Nitric Oxide / biosynthesis
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • RAW 264.7 Cells
  • Structure-Activity Relationship

Substances

  • Amides
  • Anti-Inflammatory Agents, Non-Steroidal
  • Benzamides
  • Cytokines
  • Lipopolysaccharides
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Nitric Oxide
  • EGFR protein, human
  • ErbB Receptors
  • pyrimidine