Novel probes for an important developmental signaling cascade, the Sonic Hedgehog pathway

June 10, 2013 § Leave a comment

BRD50837 is a novel small-molecule probe that inhibits Hedgehog signaling. Image by Giannina Schaefer.

BRD50837 is a novel small-molecule probe that inhibits Hedgehog signaling. Image by Giannina Schaefer.

Researchers have found novel probes that could help to better understand a critical developmental signal-transduction pathway. These probes are small-molecule inhibitors of the Sonic Hedgehog signaling pathway which, besides being essential for body segmentation in insect and vertebrate embryos, has been implicated in some cancers and developmental diseases. The work appears in the Journal of the American Chemical Society. (Yes, the name “Sonic Hedgehog” does come from the Sega video game character.)

“Many facets of the signaling network are not yet well understood,” explains Giannina Schaefer at the Broad Institute, the first author of the paper. “Small-molecule probes, especially those with novel mechanisms-of-action, may help to elucidate the biology of the signaling network.”

Some small-molecule probes for the complicated hedgehog signaling pathway do exist. One of them, vismodegib, is a drug approved by the U.S. Food and Drug Administration as a treatment of basal cell carcinoma, a cancer in which the Hedgehog pathway goes awry.

To discover new probes that could inhibit the pathway from angles inaccessible to existing probes, Schaefer and colleagues, including Stuart Schreiber of the Broad Institute who led the team, used a high-throughput, cell-based screen. “This type of cell-based screen allowed us to find inhibitors with targets at different points in the signaling network, in contrast to biochemical screens that find modulators of one particular target,” says Schaefer.

The investigators found two potent inhibitors, BRD50837 and BRD9526, that seem to interact with the Hedgehog pathway differently than existing probes when tested on a variety of different cell lines. The investigators don’t know yet with which molecules these two inhibitors are interacting in the Hedgehog pathway. But their structure/activity relationships suggests that they are selective and specific.

“Further elucidation of the mechanisms of action [of the two inhibitors] may help us understand why they perform differently,” says Schaefer. “It will increase their value as probes and possibly teach us more about the pathway.”

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