High-throughput kinase profiling: a more efficient approach toward the discovery of new kinase inhibitors

Chem Biol. 2011 Jul 29;18(7):868-79. doi: 10.1016/j.chembiol.2011.05.010.

Abstract

Selective protein kinase inhibitors have only been developed against a small number of kinase targets. Here we demonstrate that "high-throughput kinase profiling" is an efficient method for the discovery of lead compounds for established as well as unexplored kinase targets. We screened a library of 118 compounds constituting two distinct scaffolds (furan-thiazolidinediones and pyrimido-diazepines) against a panel of 353 kinases. A distinct kinase selectivity profile was observed for each scaffold. Selective inhibitors were identified with submicromolar cellular activity against PIM1, ERK5, ACK1, MPS1, PLK1-3, and Aurora A,B kinases. In addition, we identified potent inhibitors for so far unexplored kinases such as DRAK1, HIPK2, and DCAMKL1 that await further evaluation. This inhibitor-centric approach permits comprehensive assessment of a scaffold of interest and represents an efficient and general strategy for identifying new selective kinase inhibitors.

Publication types

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

MeSH terms

  • Aurora Kinases
  • Benzodiazepines / chemistry
  • Benzodiazepines / pharmacology
  • Drug Evaluation, Preclinical / methods*
  • Furans / chemistry
  • Furans / pharmacology
  • High-Throughput Screening Assays / methods*
  • Humans
  • Mitogen-Activated Protein Kinase 7 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 7 / metabolism
  • Models, Molecular
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-pim-1 / metabolism
  • Thiazolidinediones / chemistry
  • Thiazolidinediones / pharmacology

Substances

  • Furans
  • Protein Kinase Inhibitors
  • Thiazolidinediones
  • Benzodiazepines
  • 2,4-thiazolidinedione
  • Protein Kinases
  • Protein-Tyrosine Kinases
  • TNK2 protein, human
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-pim-1
  • proto-oncogene proteins pim
  • Mitogen-Activated Protein Kinase 7