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).
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
Bad food? How mesozooplankton reacts to blue-green algae blooms
17.01.2019 | Leibniz-Institut für Ostseeforschung Warnemünde
Artificially produced cells communicate with each other: Models of life
17.01.2019 | Technische Universität München
Dead and alive at the same time? Researchers at the Max Planck Institute of Quantum Optics have implemented Erwin Schrödinger’s paradoxical gedanken experiment employing an entangled atom-light state.
In 1935 Erwin Schrödinger formulated a thought experiment designed to capture the paradoxical nature of quantum physics. The crucial element of this gedanken...
Cellulose obtained from wood has amazing material properties. Empa researchers are now equipping the biodegradable material with additional functionalities to produce implants for cartilage diseases using 3D printing.
It all starts with an ear. Empa researcher Michael Hausmann removes the object shaped like a human ear from the 3D printer and explains:
The phenomenon of so-called superlubricity is known, but so far the explanation at the atomic level has been missing: for example, how does extremely low friction occur in bearings? Researchers from the Fraunhofer Institutes IWM and IWS jointly deciphered a universal mechanism of superlubricity for certain diamond-like carbon layers in combination with organic lubricants. Based on this knowledge, it is now possible to formulate design rules for supra lubricating layer-lubricant combinations. The results are presented in an article in Nature Communications, volume 10.
One of the most important prerequisites for sustainable and environmentally friendly mobility is minimizing friction. Research and industry have been dedicated...
Just in time for Christmas, a Mars-analogue mission in Morocco, coordinated by the Robotics Innovation Center of the German Research Center for Artificial Intelligence (DFKI) as part of the SRC project FACILITATORS, has been successfully completed. SRC, the Strategic Research Cluster on Space Robotics Technologies, is a program of the European Union to support research and development in space technologies. From mid-November to mid-December 2018, a team of more than 30 scientists from 11 countries tested technologies for future exploration of Mars and Moon in the desert of the Maghreb state.
Close to the border with Algeria, the Erfoud region in Morocco – known to tourists for its impressive sand dunes – offered ideal conditions for the four-week...
Research opens doors in photonic quantum information processing, optical signal processing and microwave photonics
Researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have developed a new integrated photonics platform that can...
16.01.2019 | Event News
14.01.2019 | Event News
12.12.2018 | Event News
17.01.2019 | Life Sciences
16.01.2019 | Life Sciences
16.01.2019 | Physics and Astronomy