Development of a high-content screening assay panel to accelerate mechanism of action studies for oncology research.
Efficient elucidation of the biological mechanism of action of novel compounds remains a major bottleneck in the drug discovery process. To address this need in the area of oncology, we report the development of a multiparametric high-content screening assay panel at the level of single cells to dramatically accelerate understanding the mechanism of action of cell growth-inhibiting compounds on a large scale. Our approach is based on measuring 10 established end points associated with mitochondrial apoptosis, cell cycle disruption, DNA damage, and cellular morphological changes in the same experiment, across three multiparametric assays. The data from all of the measurements taken together are expected to help increase our current understanding of target protein functions, constrain the list of possible targets for compounds identified using phenotypic screens, and identify off-target effects. We have also developed novel data visualization and phenotypic classification approaches for detailed interpretation of individual compound effects and navigation of large collections of multiparametric cellular responses. We expect this general approach to be valuable for drug discovery across multiple therapeutic areas.
Abbott Laboratories, Global Pharmaceutical Research & Development, Lead Discovery Technologies, Abbott Park, IL 60064, USA.
Danli L
DL
Towne
Emily E
EE
Nicholl
Kenneth M
KM
Comess
Scott C
SC
Galasinski
Philip J
PJ
Hajduk
Vivek C
VC
Abraham
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D004354:Drug Screening Assays, Antitumor; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D008928:Mitochondria / Q000187:drug effects
D000970:Antineoplastic Agents; D045304:Cytochromes c