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Biological Chemistry

New Technique Illuminates Small-Molecule Screening

Drug Discovery: Light not only detects cell signaling but also activates the pathway, easing inhibitor discovery

by Stu Borman
October 15, 2015 | APPEARED IN VOLUME 93, ISSUE 41

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Credit: Nat. Chem. Bio.
A technique that uses light to both activate cell signaling and monitor the results could help researchers screen libraries of small molecules for inhibitors of signaling pathways.

Researchers have found an easier way to screen for molecules that inhibit signaling pathways in cells. The new method uses light at both ends, so to speak, to activate a signaling pathway and then announce whether signal propagation proceeded successfully.

The technique could speed screening for drug discovery because it doesn’t need synthetic small molecules or endogenous receptor ligands to activate pathways or added reporting agents to monitor signals. The assay also obviates the need to know the pathway’s molecular mechanism.

Harald Janovjak of the Institute of Science & Technology Austria and coworkers used the method to analyze a pathway controlled by human ROS1, a signaling receptor that’s an anticancer target but whose natural ligand is unknown (Nat. Chem. Biol. 2015, DOI: 10.1038/nchembio.1933). They introduced two engineered genetic sequences into human embryonic kidney cells: one coding for a version of ROS1 that initiates signaling when hit by blue light, and another for genes that respond to ROS1 signaling by expressing green fluorescent protein. Light from the fluorescent protein, or lack thereof when an effective inhibitor is present, can be monitored easily. Using a fluorescent reporter in screening is not unusual, but combining it with light-based signal activation is unique, Janovjak says.

The team used the technique to screen a library of small molecules and found three inhibitors of the ROS1 pathway, including an anticancer agent called AV-951 (tivozanib) that has been studied in clinical trials and whose ability to inhibit ROS1 signaling was previously unknown. The researchers believe the all-optical screening approach can be adapted to many other drug targets and cellular processes.

“While the final verdict is still out, the work lights the way toward a new modality of small-molecule screening,” says Andreas Möglich, an expert on photoreceptors at the University of Bayreuth, in Germany. He notes that activating a pathway with light has advantages over using small molecules or other ligands to do so because it permits screening to be more easily automated and will lead to more reproducible outcomes. The technique could readily be extended to other drug targets such as ion channels, he adds.

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