An efficient rapid system for profiling the cellular activities of molecular libraries

Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3153-8. doi: 10.1073/pnas.0511292103. Epub 2006 Feb 21.

Abstract

Rapid quantitative methods for characterizing small molecules, peptides, proteins, or RNAs in a broad array of cellular assays would allow one to discover new biological activities associated with these molecules and also provide a more comprehensive profile of drug candidates early in the drug development process. Here we describe a robotic system, termed the automated compound profiler, capable of both propagating a large number of cell lines in parallel and assaying large collections of molecules simultaneously against a matrix of cellular assays in a highly reproducible manner. To illustrate its utility, we have characterized a set of 1,400 kinase inhibitors in a panel of 35 activated tyrosine-kinase-dependent cellular assays in dose-response format in a single experiment. Analysis of the resulting multidimensional dataset revealed subclusters of both inhibitors and kinases with closely correlated activities. The approach also identified activities for the p38 inhibitor BIRB796 and the dual src/abl inhibitor BMS-354825 and exposed the expected side activities for Glivec/STI571, including cellular inhibition of c-kit and platelet-derived growth factor receptor. This methodology provides a powerful tool for unraveling the cellular biology and molecular pharmacology of both naturally occurring and synthetic chemical diversity.

MeSH terms

  • Animals
  • Automation
  • Cell Line
  • Databases, Factual
  • Drug Evaluation, Preclinical / methods
  • Mice
  • Phosphotransferases / antagonists & inhibitors*
  • Phosphotransferases / genetics
  • Phosphotransferases / metabolism*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / isolation & purification
  • Protein Kinase Inhibitors / pharmacology*
  • Reproducibility of Results
  • Robotics / methods*
  • Structure-Activity Relationship
  • Time Factors

Substances

  • Protein Kinase Inhibitors
  • Phosphotransferases