The ability of an experimental drug known as GW5638 to change the shape of the estrogen receptor is helping researchers understand why drugs like tamoxifen and raloxifene behave the way they do, simulating the effects of estrogen in some tissues and blocking it in others.

The finding indicates that this little-known drug may play an important role in preventing, as well as treating, breast cancer and suggests ways to design new drugs with even more specific effects.

Writing in the journal Molecular Cell, researchers from the University of Chicago, Renz Research, Inc., Duke University and GlaxoSmithKline show how GW5638 fits into a pocket in the estrogen receptor in a way that differs slightly, but importantly, from how tamoxifen fits. The slight difference changes the shape of the receptor in ways that alter its effects on the numerous coregulatory proteins that interact with it.

"We found a small, but significant, change in conformation that goes a long way towards explaining why these drugs have different effects in different tissues," said Geoffrey Greene, Ph.D., professor in the Ben May Institute for Cancer Research at the University of Chicago.

"This type of information should help us design drugs that produce even more specific outcomes. In particular, we could design new small molecules that would be more effective than tamoxifen or raloxifene at preventing breast cancer, heart disease and bone loss without increasing the risk of endometrial cancer."

Tamoxifen and raloxifene are the best-known members of a class of drugs known as specific estrogen receptor modulators or SERMs. These drugs mimic some effects of estrogen and block others. For example, tamoxifen blocks the effects of estrogen in the breast and thus is widely used to treat and prevent breast cancers that depend on estrogen. But it has the opposite effect in the uterus, acting like estrogen to stimulate tissue growth and increasing the risk of uterine cancer.

A newer group of drugs, known as selective estrogen receptor down-regulators, or SERDs, have a more potent anti-estrogen effect, involving destabilization of the estrogen receptor, which leads to its degradation.

GW5638 fits somewhere in the middle, acting like a SERM in some tissues and more like a SERD in others, including mammary tissue, where it is a powerful estrogen antagonist. As a consequence, GW 5638 can inhibit the growth of breast cancers that have become resistant to tamoxifen. It may also be more effective than tamoxifen at preventing cancer in women at high risk.

SOURCES:
Molecular Cell, May 13, 2005
University of Chicago Medical Center (http://www.uchospitals.edu)