Kinetic cell-based morphological screening: prediction of mechanism of compound action and off-target effects.
We describe a cell-based kinetic profiling approach using impedance readout for monitoring the effect of small molecule compounds. This noninvasive readout allows continuous sampling of cellular responses to biologically active compounds and the ensuing kinetic profile provides information regarding the temporal interaction of compounds with cells. The utility of this approach was tested by screening a library containing FDA approved drugs, experimental compounds, and nature compounds. Compounds with similar activity produced similar impedance-based time-dependent cell response profiles (TCRPs). The compounds were clustered based on TCRP similarity. We identified novel mechanisms for existing drugs, confirmed previously reported calcium modulating activity for COX-2 inhibitor celecoxib, and identified an additional mechanism for the experimental compound monastrol. We also identified and characterized a new antimitotic agent. Our findings indicate that the TCRP approach provides predictive mechanistic information for small molecule compounds.
Abassi
Yama A
YA
ACEA Biosciences, 6779 Mesa Ridge Road, San Diego, CA 92121, USA. yabassi@aceabio.com
Xi
Biao
B
Zhang
Wenfu
W
Ye
Peifang
P
Kirstein
Shelli L
SL
Gaylord
Michelle R
MR
Feinstein
Stuart C
SC
Wang
Xiaobo
X
Xu
Xiao
X
D016000:Cluster Analysis; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D017097:Electric Impedance; D004566:Electrodes; D007700:Kinetics; D054852:Small Molecule Libraries / Q000494:pharmacology
D054852:Small Molecule Libraries