Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

TCD researchers chart chemical space in the search for new breast cancer treatments

27.11.2006
Centre for Synthesis and Chemical Biology researcher Dr Mary Meegan from the School of Pharmacy and Pharmaceutical Sciences in Trinity College Dublin with collaborators Drs Andrew Knox and David Lloyd have used computational methods to identify new leads for treating breast cancer. When tested against estrogen receptor (ER) positive cancer cell lines, 12 of the compounds performed up to 100 times better than Tamoxifen.

Estrogen and the estrogen receptor (ER)

"Estrogen works by locking into the ER, causing a change to the shape of the receptor," explains Dr Meegan. "This structural change enables the estrogen-receptor complex to bind to coactivator proteins and initiate a cascade of downstream effects resulting in cell proliferation."

Estrogen promotes cell proliferation in the breast and uterus but in breast cells with DNA mutations this process can increase the risk of developing breast cancer. This increased risk was already shown in studies involving the administration of estrogen to reduce cholesterol and maintain bone density in hormone replacement therapy (HRT).

... more about:
»Cancer »Estrogen »Meegan »Tamoxifen »antiestrogen »receptor

Tamoxifen and Raloxifene

Two of the current Selective Estrogen Receptor Modulator (SERM) drugs, Tamoxifen and Raloxifene, are antiestrogens and are used for treating breast cancer and osteoporosis respectively.

Tamoxifen mimics estrogen by preventing its binding to estrogen receptors in breast cells, but it can activate estrogen receptors in the uterus and long-term use is associated with a small increase in the risk of uterine cancer. However, it remains one of the endocrine drugs of choice for the treatment of breast cancer. Raloxifene in contrast reduces the risk of endometrial cancer and is currently used to treat osteoporosis.

Both drugs have benefits and limitations and a clinical trial called the Study of Tamoxifen and Raloxifene (STAR), due to finish this year, aims to evaluate their ability to prevent breast cancer in women who are at high risk of developing the disease.

"There is a requirement for new antiestrogen molecules that have improved specificity and toxicology profiles. We are working to identify molecules that are selective at the estrogen receptors in breast cells but which don't have a proliferative effect in other tissues," continues Dr Meegan.

Discovering new leads using structure-based drug design

Dr Meegan's group takes a practical approach to discovering potential leads for drugs. The estrogen receptor holds the key because its crystal structure and how it binds to antiestrogens is well documented. Using computational methods researchers can screen potential leads by studying their 3D conformations and binding properties.

"We group molecules with specific cancer activity together and analyse them in chemical space," continues Dr Meegan. "As part of his PhD thesis Dr Andrew Knox devised a scoring system to rate molecular fit in the estrogen receptor so we can accurately predict new leads."

Dr Knox screened thousands of molecules from drug databases using his own screening methods. He was able to narrow the search by devising a ranked hitlist where molecules with the highest score were identified for further exploration and biochemical testing. The next step in the drug discovery process was to set up a synthetic programme to explore the structure of the molecules and to design and synthesise analogues for further testing.

Dr Meegan's research group is working to develop efficient synthetic routes to the various series of compound structures identified by Dr Knox. They have tested them against ER positive, ER negative and uterine cancer lines to confirm that their action is mediated through the ER.

"The results so far have been very encouraging in that a number of the compounds identified perform better than Tamoxifen as antiestrogens and are showing no adverse effect in uterine cells. We are currently working to optimize the selective binding properties of these antiestrogenic compounds and to elucidate the mechanism of antihormonal resistance," concludes Dr Meegan.

Orla Donoghue | alfa
Further information:
http://www.ucd.ie/cscb/

Further reports about: Cancer Estrogen Meegan Tamoxifen antiestrogen receptor

More articles from Life Sciences:

nachricht Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University

nachricht How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Can the immune system be boosted against Staphylococcus aureus by delivery of messenger RNA?

Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.

Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....

Im Focus: A quantum walk of photons

Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.

The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....

Im Focus: Turmoil in sluggish electrons’ existence

An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.

We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...

Im Focus: Wafer-thin Magnetic Materials Developed for Future Quantum Technologies

Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.

Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...

Im Focus: World's thinnest hologram paves path to new 3-D world

Nano-hologram paves way for integration of 3-D holography into everyday electronics

An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Marine Conservation: IASS Contributes to UN Ocean Conference in New York on 5-9 June

24.05.2017 | Event News

AWK Aachen Machine Tool Colloquium 2017: Internet of Production for Agile Enterprises

23.05.2017 | Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

 
Latest News

How herpesviruses win the footrace against the immune system

26.05.2017 | Life Sciences

Water forms 'spine of hydration' around DNA, group finds

26.05.2017 | Life Sciences

First Juno science results supported by University of Leicester's Jupiter 'forecast'

26.05.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>