Discovery of novel 4-amino-6-arylaminopyrimidine-5-carbaldehyde oximes as dual inhibitors of EGFR and ErbB-2 protein tyrosine kinases

Bioorg Med Chem Lett. 2008 Jun 15;18(12):3495-9. doi: 10.1016/j.bmcl.2008.05.024. Epub 2008 May 10.

Abstract

We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC(50) values in the nanomolar range. Structure-activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Binding Sites / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / chemistry*
  • Humans
  • Hydrogen Bonding
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Oximes / chemical synthesis
  • Oximes / chemistry
  • Oximes / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Oximes
  • Pyrimidines
  • EGFR protein, human
  • ErbB Receptors
  • Receptor, ErbB-2