Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Research reveals potential new target for prostate cancer drugs

24.08.2004


This atomic-level model of part of the human androgen receptor shows the target for a potential drug against prostate cancer. New research has determined the three-dimensional, atom-by atom structure of the target. The drug would bind to the receptor, interrupting its activity which drives the disease.


Scientists have determined the precise molecular structure of a potential new target for treating prostate cancer, a disease driven in part by abnormal testosterone activity. The target is part of the androgen receptor, a protein essential for testosterone to function in human cells. Prostate cancer is the most common cancer among men.

The androgen receptor and testosterone – technically, 5-alpha dihydrotestosterone – each drive prostate cancer at different stages of the disease. A common prostate cancer treatment uses drugs that compete with testosterone, blocking its ability to bind with the androgen receptor and so reducing the hormone’s effect. But cancer tends to become resistant to these drugs. The new research provides a novel strategy to block activation of both the androgen receptor and testosterone.

UCSF scientists determined the atom-by-atom topography of the pocket where proteins known as coactivators bind to the human androgen receptor to enable testosterone to trigger gene activity. Knowing the detailed shape greatly boosts the likelihood of developing a drug to block this binding and turn off androgen receptor activity, the scientists report.



The research is being published online August 24 by Public Library of Science (PLoS) Biology. "Drugs that block testosterone binding are not effective in the long term against prostate cancer," says Robert Fletterick, PhD, UCSF professor of biochemistry and biophysics and senior author on the PloS Biology paper. "The shape of the site we have determined – where coactivators bind to the androgen receptor – specifies the design for a new class of drugs. Simple versions of the ’ultimate’ drug will be tested in cancer cells this year." With an aggressive search for the right chemicals, candidate drugs might be tested in human patients within three years, he says.

UCSF has filed for a patent revealing the nature of the coactivator site on the androgen receptor.

Fletterick, whose laboratory is based at UCSF’s Mission Bay campus, is a researcher in the California Institute for Quantitative Biomedical Research, or QB3. He collaborates with clinical cancer scientists at UCSF, and the new research is supported by an NIH SPORE grant (for Specialized Program of Research Excellence), which funds programs that effectively integrate basic research, such as Fletterick’s, with clinical research aimed at developing new clinical treatments. Fletterick’s UCSF clinical research colleagues are eager to work on developing treatments if coactivator-blocking drugs can be developed, he says.

The male hormone testosterone controls development and maintenance of the male reproductive system and other tissues such as bone and muscle. The hormone is present in smaller amounts in females, where it also helps form muscle and bones.

The scientists determined the shape of the binding pocket on the androgen receptor – technically, the coactivator binding interface – by exposing it to billions of randomly chosen protein fragments, or peptides, and selecting for those that bind best. They then imaged the peptides that bind best using a technology called X-ray diffraction that shows every atom of the peptide and the receptor, and how they interact.

The researchers are now testing the ability of different small molecules to bind to the androgen receptor binding site. They hope to demonstrate the potential of developing a drug that will bind more strongly than the normal coactivator, thereby shutting down androgen receptor activity.

Knowing the molecular shape of the target speeds development of a new drug about ten-fold, Fletterick says, and helps assure that the drug will work as expected. The new structural information from the limited number of peptides and small molecules that bind well to the coactivator sites can be used by chemists to screen from among thousands of "best-fitting" molecules to find those with the precise configuration and traits needed for a good drug to block coactivator binding, Fletterick says. In addition, chemists can use the information to synthesize new molecules with the required drug traits.

It remains uncertain whether researchers can identify a small molecule drug candidate that binds to the coactivator more strongly than the coactivators themselves do, Fletterick cautions.

Cancer researchers do not know which coactivators bind with the androgen receptor when cancer strikes, Fletterick adds. But the research may lead to selective drugs that permit "good" activators to bind while blocking those that promote cancer progression. This possibility is the focus of new research by several UCSF labs.

The highly detailed structure of the coactivator binding site revealed by the research explains the unusual behavior of this hormone’s receptor, says Eugene Hur, BS, UCSF graduate student in biophysics and lead author of the scientific paper. Most hormone receptors bind to coactivator sequences rich in the amino acid leucine, but the androgen receptor is unique in preferring bigger, bulkier bonding partners. The explanation appears to lie in the unusually deep binding region, the scientists report.

Co-authors on the paper, along with Fletterick and Hur, are Samuel J. Pfaff, BS, graduate student in biophysics at UCSF; E. Sturgis Payne, research staff; Hanne Gron, PhD, research scientist; and Benjamin M. Buehrer, PhD, project leader, all at Karo Bio in Durham, North Carolina.

Wallace Ravven | EurekAlert!
Further information:
http://www.ucsf.edu

More articles from Life Sciences:

nachricht What the world's tiniest 'monster truck' reveals
23.08.2017 | American Chemical Society

nachricht Treating arthritis with algae
23.08.2017 | Empa - Eidgenössische Materialprüfungs- und Forschungsanstalt

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

What the world's tiniest 'monster truck' reveals

23.08.2017 | Life Sciences

Treating arthritis with algae

23.08.2017 | Life Sciences

Witnessing turbulent motion in the atmosphere of a distant star

23.08.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>