In the May 13, 2005, issue of 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
Contact: John Easton
University of Chicago Medical Center