Structure-based design and synthesis of covalent-reversible inhibitors to overcome drug resistance in EGFR

Bioorg Med Chem. 2015 Jun 15;23(12):2767-80. doi: 10.1016/j.bmc.2015.04.038. Epub 2015 Apr 23.

Abstract

The clinical success of covalent kinase inhibitors in the treatment of EGFR-dependent non-small cell lung cancer (NSCLC) has rejuvenated the appreciation of reactive small molecules. Acquired drug resistance against first-line EGFR inhibitors remains the major bottleneck in NSCLC and is currently addressed by the application of fine-tuned covalent drugs. Here we report the design, synthesis and biochemical evaluation of a novel class of EGFR inhibitors with a covalent yet reversible warhead. A series of WZ4002 analogs, derived from anilinopyrimidine and 3-substituted-2-cyanoacrylamide scaffolds, exhibit strong and selective inhibitory activity against clinically relevant EGFR(L858R) and EGFR(L858R/T790M).

Keywords: Covalent-Reversible Inhibitor; Kinases; Lung cancer; Medicinal chemistry; Receptor tyrosine kinases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Acrylamides
  • Protein Kinase Inhibitors
  • Pyrimidines
  • WZ4002
  • ErbB Receptors