Synthesis and characterization of novel quinazoline type inhibitors for mutant and wild-type EGFR and RICK kinases

J Recept Signal Transduct Res. 2008;28(4):361-73. doi: 10.1080/10799890802242618.

Abstract

The development of selective protein kinase inhibitors has become an important area of drug discovery for the treatment of different diseases. We report the synthesis and characterization of a series of novel quinazoline derivatives against three therapeutically important and pharmacologically related kinases: 1) epidermal growth factor receptor (EGFR; wild type and mutant) in the field of cancer, 2) receptor-interacting caspase-like apoptosis-regulatory kinase (RICK) in the field of inflammation, and 3) pUL97 of human cytomegalovirus (HCMV). For reference purpose we have synthesized the four clinically relevant quinazolines, including the lead compounds, which we previously identified for RICK and pUL97. A total of 52 quinazoline derivatives were synthesized and tested on the basis of these leads to specifically target the hydrophobic pocket of the ATP-binding site. Selected compounds were tested on wild-type and mutant forms of EGFR, RICK, and pUL97 kinases; their logP and logS values for assessing suitability as drugs were calculated and hit or lead compounds identified.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytomegalovirus
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Humans
  • Mutant Proteins / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / metabolism
  • Quinazolines / pharmacology*
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / antagonists & inhibitors*
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / metabolism
  • Viral Proteins / antagonists & inhibitors
  • Viral Proteins / drug effects
  • Viral Proteins / metabolism*

Substances

  • Mutant Proteins
  • Protein Kinase Inhibitors
  • Quinazolines
  • Viral Proteins
  • Phosphotransferases (Alcohol Group Acceptor)
  • ganciclovir kinase
  • ErbB Receptors
  • Receptor-Interacting Protein Serine-Threonine Kinase 2