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 Kidney tumor: Genetic trigger discovered
18.06.2018 | Julius-Maximilians-Universität Würzburg

nachricht New type of photosynthesis discovered
18.06.2018 | Imperial College London

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

Im Focus: Photoexcited graphene puzzle solved

A boost for graphene-based light detectors

Light detection and control lies at the heart of many modern device applications, such as smartphone cameras. Using graphene as a light-sensitive material for...

Im Focus: Water is not the same as water

Water molecules exist in two different forms with almost identical physical properties. For the first time, researchers have succeeded in separating the two forms to show that they can exhibit different chemical reactivities. These results were reported by researchers from the University of Basel and their colleagues in Hamburg in the scientific journal Nature Communications.

From a chemical perspective, water is a molecule in which a single oxygen atom is linked to two hydrogen atoms. It is less well known that water exists in two...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

Novel method for investigating pore geometry in rocks

18.06.2018 | Earth Sciences

Diamond watch components

18.06.2018 | Process Engineering

New type of photosynthesis discovered

18.06.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>