Automated imaging screen reveals promising drug candidates


Two closely related compounds produced the morphological differences evident in these lung cancer cells, and reveal biological activity that could be important for drug discovery. (Image: Copyright Cytokinetics, Inc.)
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The birth of combinatorial chemistry in the early 1990s held out the promise that scientists would soon synthesize trillions of compounds at a time and screen up to a million a day, revolutionizing the process of drug discovery. But synthesizing a vast library of compounds is just the first step in the historically painstaking process of determining whether a compound has the desired effect on a target. In addition to an ever-growing library of candidate therapeutic compounds, advances in genome analysis have produced a growing list of potential drug targets - drowning drug researchers in an excess of riches.

In the open-access journal PLoS Biology, Kevan Shokat and colleagues report a high-throughput screening method that substantially narrows the field of candidate therapeutic agents. Their approach takes advantage of a recently developed automated system (called Cytometrix) that combines advanced imaging and bioinformatics approaches to classify cells according to small-molecule-induced changes in cell size, shape, and structure (morphology). Their analysis identified a novel compound with promising potential as an anticancer agent.

From the library of screened compounds, Shokat and colleagues identified a molecule (hydroxy-PP) that, though structurally related to a known kinase inhibitor, induced morphological changes distinct from any known kinase inhibitor. What does hydroxy-PP target? An enzyme, called carbonyl reductase 1 (CBR1), that acts on xenobiotics like anticancer drugs and is thought to cause the heart damage associated with daunorubicin chemotherapy.

The authors then solved the structure of hydroxy-PP and CBR1 bound together and used their structural analysis to increase hydroxy-PP's inhibition of CBR1 in cell culture so they could further explore the enzyme's biological function. These experiments revealed a previously uncharacterized role for CBR1 in programmed cell death.

Given the enzyme's suspected role in chemotherapy-related cardiotoxicity, inhibiting CBR1 activity might enhance the efficacy of chemotherapy treatments by reducing their debilitating side effects-a possibility that future studies can explore. But for now, Shokat and colleagues have demonstrated the power of using high-throughput image-based screening to identify small molecules both for probing cell biology and for identifying promising drug candidates.

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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