Identification of two novel RET kinase inhibitors through MCR-based drug discovery: design, synthesis and evaluation

Eur J Med Chem. 2014 Oct 30:86:714-23. doi: 10.1016/j.ejmech.2014.09.023. Epub 2014 Sep 8.

Abstract

From an MCR fragment library, two novel chemical series have been developed as inhibitors of RET, which is a kinase involved in the pathology of medullary thyroid cancer (MTC). Structure activity relationship studies (SAR) identified two sub-micromolar tractable leads, 6g and 13g. 6g was confirmed to be a Type-II RET inhibitor. 13g and 6g inhibited RET in cells transformed by RET/C634. A RET DFG-out homology model was established and utilized to predict Type-II inhibitor binding modes.

Keywords: Kinase; Lead discovery; MCR; Medicinal chemistry; RET; Targeted therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-ret / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-ret / metabolism
  • Structure-Activity Relationship

Substances

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