Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Tamoxifen-like drug suggests new ways to selectively block estrogen


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.

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.

John Easton | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht First time-lapse footage of cell activity during limb regeneration
25.10.2016 | eLife

nachricht Phenotype at the push of a button
25.10.2016 | Institut für Pflanzenbiochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Etching Microstructures with Lasers

Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.

This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...

Im Focus: Light-driven atomic rotations excite magnetic waves

Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion

Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Ice shelf vibrations cause unusual waves in Antarctic atmosphere

25.10.2016 | Earth Sciences

Fluorescent holography: Upending the world of biological imaging

25.10.2016 | Power and Electrical Engineering

Etching Microstructures with Lasers

25.10.2016 | Process Engineering

More VideoLinks >>>