title: Kinetic cell-based morphological screening: prediction of mechanism of compound action and off-target effects.
abstract: 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.
authors.affiliation: ACEA Biosciences, 6779 Mesa Ridge Road, San Diego, CA 92121, USA. yabassi@aceabio.com
authors.forename: Yama A
authors.initials: YA
authors.lastname: Abassi
authors.forename: Biao
authors.initials: B
authors.lastname: Xi
authors.forename: Wenfu
authors.initials: W
authors.lastname: Zhang
authors.forename: Peifang
authors.initials: P
authors.lastname: Ye
authors.forename: Shelli L
authors.initials: SL
authors.lastname: Kirstein
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Gaylord
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Feinstein
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wang
authors.forename: Xiao
authors.initials: X
authors.lastname: Xu
mesh_terms: 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
chemical_list: D054852:Small Molecule Libraries