GW5638 uniquely alters the shape of the estrogen receptor

An experimental drug developed in the early 1990s called GW5638 has helped researchers better understand why and how cancer-fighting drugs like tamoxifen are able to impact some types of breast cancer. Geoffrey Greene, Ph.D., Professor in the Ben May Department for Cancer Research, has conducted research that demonstrates how GW5638 uniquely alters the shape of the estrogen receptor and thus interacts differently with the estrogen receptor protein found in various hormone sensitive tissues.

"GW5638 fits in the niche between selective estrogen receptor modulators (SERMs) like tamoxifen and selective estrogen receptor down-regulators (SERDs) like fulvestrant, which destabilize the estrogen receptor," says Greene. "This drug has elements of both and can inhibit breast cancers when the disease has become resistant to tamoxifen treatment.

GW5638 binds to the estrogen receptor in the same location as tamoxifen and estradiol, but induces a unique conformation of the receptor. After binding takes place, the protein is twisted, dislocating a peptide spiral called helix 12. Once this displacement occurs, the estrogen receptor interacts differently with other downstream effector molecules called coregulators.

"We know that helix 12 is a molecular switch and that it is part of a hydrophobic coactivator docking sight," Greene continues. "In the presence of SERMs like tamoxifen, helix 12 actually occupies this hyrophobic cleft and prevents the recruitment of coactivators. This is also the case with the GW compound, but with this drug helix 12 has a very different orientation, involving both a repositioning and a twisting of this helix, so that a more hydrophobic surface is presented."

THe GW compound also destabilizes the estrogen receptor, and Green and his team found a direct relationship between hydrophobicity and this destabilization of the receptor.

"Because this drug differentially targets testrogen receptors in specific tissues, there are profound clinical implications," Greene explains. "For instance, GW5638 does not increase the chance of developing uterine cancer, as tamoxifen does, but it does maintain bone density, like estradiol. Ultimately, this drug could help us discover ways of tailoring drug prevention or treatment strategies for homone dependent cancers that also benefit other tissues throughout the body."

Results from this study were published in the May 13, 2005, issue of Molecular Cell (Vol.18, Issue 4, 413-424).