GSK114: A selective inhibitor for elucidating the biological role of TNNI3K

Bioorg Med Chem Lett. 2016 Jul 15;26(14):3355-3358. doi: 10.1016/j.bmcl.2016.05.033. Epub 2016 May 14.

Abstract

A series of selective TNNI3K inhibitors were developed by modifying the hinge-binding heterocycle of a previously reported dual TNNI3K/B-Raf inhibitor. The resulting quinazoline-containing compounds exhibit a large preference (up to 250-fold) for binding to TNNI3K versus B-Raf, are useful probes for elucidating the biological pathways associated with TNNI3K, and are leads for discovering novel cardiac medicines. GSK114 emerged as a leading inhibitor, displaying significant bias (40-fold) for TNNI3K over B-Raf, exceptional broad spectrum kinase selectivity, and adequate oral exposure to enable its use in cellular and in vivo studies.

Keywords: B-Raf; Kinase selectivity; Quinazoline; Substituent effects; TNNI3K.

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • MAP Kinase Kinase Kinases / metabolism
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*

Substances

  • GSK114
  • Protein Kinase Inhibitors
  • Quinazolines
  • Sulfonamides
  • Protein Serine-Threonine Kinases
  • TNNI3K protein, human
  • MAP Kinase Kinase Kinases