Structural modification of an EGFR inhibitor that showed weak off-target activity against RET leading to the discovery of a potent RET inhibitor

Mol Divers. 2014 May;18(2):403-9. doi: 10.1007/s11030-014-9508-8. Epub 2014 Feb 11.

Abstract

Here, we describe the structural optimization of a known EGFR inhibitor (compound 1) that showed weak off-target activity against RET. Twenty-six analogs of 1 were synthesized. SAR analysis led to the discovery of several compounds that showed considerable potency against the RET-dependent thyroid cancer cell line TT. Kinase inhibitory potency was then measured for the most active compound (2u) in the cellular assay. The results showed that 2u is a potent RET inhibitor with an IC(50) value of 7 nM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Discovery*
  • ErbB Receptors / antagonists & inhibitors*
  • Hep G2 Cells
  • Humans
  • Inhibitory Concentration 50
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-ret / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • ErbB Receptors
  • Proto-Oncogene Proteins c-ret