Many breast cancer drugs block estrogen receptors inside cancer cells. Blocking the receptors early in disease progression staves off metastasis. But most patients with advanced disease eventually develop drug resistance, leaving doctors desperate for alternatives. Now, researchers have uncovered a previously uncharacterized, bridge-like structure within the human estrogen receptor that could serve as a valuable new drug target. In Nature Communications, researchers describe a "burning the bridge" strategy to disrupting the estrogen receptor, and how to screen breast cancer drugs designed to do it.
"Until now, the structure of the entire estrogen receptor complex was unknown, so it was a challenge to identify novel or functionally important target sites for new drugs," said the senior author on the study. "The structures of individual receptor pieces were known, but how they fit together was a mystery. Our study identified a novel interface that bridges the two major functional units of the receptor."
The "bridge" identified in the new study links two key receptor parts: one that binds estrogen, and one that attaches to DNA and controls genes in response to estrogen levels. Drugs that disrupt the bridge could affect how the two portions are able to work together, inhibiting receptor function. Said the senior author, "Disruption of the bridge prevents the two major parts of the estrogen receptor complex from communicating, so targeting this interface represents a 'burning-the-bridge' strategy for drug discovery."
The new study further suggests that the bridge can be exploited as a novel drug target. By genetically engineering fluorescent probes to normal receptors in their laboratory, the team was able to tell when the two critical parts of the receptor were communicating properly. The set-up represents a new assay to screen small molecule drugs designed to therapeutically inhibit estrogen receptor function inside cancer cells.
Already the researchers have begun to test drug molecules using their new assay. They also plan to screen libraries of drugs already FDA-approved. "This approach can jump-start drug discovery, by identifying drugs that can be re-purposed to target breast cancer," the senior author said. Moreover, since the receptor has structural similarities to other hormone receptors central to ovarian, prostate, and endometrial cancers, the new study and the assay could have widespread implications for drug discovery.
'Burning the bridge" strategy to identify cancer drug candidates to block estrogen receptor
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