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A Fluorescence-based Lymphocyte Assay Suitable for High-throughput Screening of Small Molecules
Published on: March 10, 2017
An unbiased cell morphology-based screen for new, biologically active small molecules
Masahiro Tanaka1, Raynard Bateman, Daniel Rauh
1Department of Cellular and Molecular Pharmacology, University of California, San Francisco, USA.
Plos Biology
|April 1, 2005
Summary
We discovered a new way to find small molecules that change cell shape, leading to the identification of carbonyl reductase 1 (CBR1) as a target. This finding offers new anticancer drug candidates and insights into cell death pathways.
Area of Science:
- Chemical Biology
- Cell Biology
- Drug Discovery
Background:
- Automated cell imaging and analysis systems enable unbiased screening of small molecules.
- Morphological profiling can identify modulators of cellular processes and reveal unknown pathways.
Purpose of the Study:
- To implement an unbiased cell morphology-based screen for identifying small-molecule modulators.
- To discover novel targets and biological functions of small molecules using phenotypic screening.
Main Methods:
- Utilized Cytometrix automated imaging and analysis for cell morphology screening.
- Treated cancer cell lines with diverse small molecules and analyzed phenotypic readouts.
- Employed multivariate statistical analysis and principal component analysis for compound classification.
- Identified target of a novel compound (hydroxy-PP) using affinity purification and X-ray crystallography.
Main Results:
- Identified carbonyl reductase 1 (CBR1) as a novel target of hydroxy-PP.
- Determined the X-ray crystal structure of the CBR1/hydroxy-PP complex.
- Developed potent and selective CBR1 inhibitors for biological studies.
- Revealed a previously unknown role for CBR1 in serum-withdrawal-induced apoptosis.
- Demonstrated that CBR1 inhibitors may enhance anthracycline anticancer efficacy.
Conclusions:
- Morphology-based screening is a powerful method for discovering small-molecule probes and anticancer drug candidates.
- CBR1 plays a significant role in apoptosis and represents a potential therapeutic target.
- Novel CBR1 inhibitors show promise for combination cancer therapy.
