1. Academic Validation
  2. Structure-based design and synthesis of covalent-reversible inhibitors to overcome drug resistance in EGFR

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.
Debjit Basu 1 André Richters 1 Daniel Rauh 2
Affiliations

Affiliations

  • 1 Department of Chemistry and Chemical Biology, Technische Universität Dortmund, Otto-Hahn-Straße 6, 44227 Dortmund, Germany.
  • 2 Department of Chemistry and Chemical Biology, Technische Universität Dortmund, Otto-Hahn-Straße 6, 44227 Dortmund, Germany. Electronic address: daniel.rauh@tu-dortmund.de.
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.

Figures