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 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.
Equally important was learning how the very slight difference between tamoxifen and GW5638 altered the interactions between the estrogen receptor and other molecules that are regulated by the estrogen receptor.
Estrogen, tamoxifen and GW5638 all bind to the estrogen receptor in the same "pocket," but after binding they change the shape, or conformation, of the receptor in different ways. GW5638 pushes one small part of the estrogen receptor, a peptide spiral called helix 12, out of place. By shifting helix 12 to an odd spot, GW5638 disrupts the ways in which several other molecules that normally interact with the estrogen receptor go about their jobs.
These molecules, called coactivators or corepressors, can enhance or repress the effects of estrogen. They are present at different levels in different tissues.
"H12 positioning is essential for these interactions," Greene said. "By changing the conformation of the estrogen receptor, this drug changes the way it interacts with a whole series of related downstream molecules. And those interactions explain why these drugs have different effects in different locations, such as breast, bone or uterus."
This finding opens a new arena for drug design, suggests Greene. Nuclear receptors, such as the estrogen receptor, are major drug targets, accounting for more than 20 percent of all drugs. This finding suggests "we could move beyond 'designer estrogens,' to all sorts of small molecules that mimic the actions of various hormones," Greene said. "We could create designer androgens for prostate cancer, or designer glucocorticoids to treat inflammation."
Since "the primary regulator of cofactor recruitment is receptor conformation," added study co-author Donald McDonnell of Duke, findings such as this should lead to the emergence of "a new wave of estrogen receptor modulators with improved specificity. We are moving, he said, "very close to the day where a proteomic profile of a tumor will determine the best SERM or SERD or other endocrine therapy that will yield maximal benefit in the clinic."
New tools such as the Advanced Photon Source at Argonne National Laboratories are making this sort of once-grandiose plan more realistic, Greene said. "We used to solve the structures of one or two molecules a year. Now we have 40 to 50 in progress."
GW5638 was developed as a variation on tamoxifen in the early 1990s by co-author Tim Willson and colleagues at what was then Glaxo Wellcome, hence the name GW5638. McDonnell, at Duke, recognized its potential and demonstrated efficacy in animal models of tamoxifen-resistant breast cancer. The drug has completed initial phase I clinical testing and has garnered significant interest from the pharmaceutical industry.
The Ludwig Fund for Cancer Research, the National Institutes of Health, and the Department of Defense funded this study. Additional authors were Ya-Ling Wu from the University of Chicago; Xiaojung Yang and Zhong Ren from Renz Research, Inc., in Westmont, IL; John Norris from Duke; and Timothy Willson from GlaxoSmithKline, in Research Triangle Park, NC.