Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Research Involving Thyroid Hormone Lays Foundation for More Targeted Drug Development

25.10.2011
Research led by St. Jude Children’s Research Hospital scientists advances a strategy for taming the side effects and enhancing the therapeutic benefits of steroids and other medications that work by disrupting the activity of certain hormones.

The approach relies on a small molecule developed at St. Jude. In this study, scientists showed that a compound known as SJ-AK selectively blocked the activity of genes in a cell signaling pathway regulated by thyroid hormone.

Investigators showed that SJ-AK also affected cells growing in the laboratory, reducing cell proliferation as well as the production and secretion of a growth hormone regulated by thyroid hormone. The research appears in the October issue of the scientific journal ACS Chemical Biology.

The findings raise hope that compounds like SJ-AK will lead to drugs with more tailored effects by selectively controlling signaling pathways that switch genes on and off. This research focused on a pathway controlled by a thyroid hormone. Investigators said, however, the approach also could potentially be used to target pathways regulated by glucocorticoid, estrogen, androgen and other hormones that are widely used to treat cancer and other conditions but that also have serious side effects.

“This study offers the first evidence it is possible to shut down a portion of the signaling network activated by a particular hormone,” said R. Kiplin Guy, Ph.D., chair of the St. Jude Chemical Biology and Therapeutics Department. Guy is the senior author. The first author is Prabodh Sadana, Ph.D., a former St. Jude postdoctoral fellow who now works in the Department of Pharmaceutical Sciences at Northeastern Ohio Universities College of Medicine and Pharmacy.

Such selectivity could lead to a new generation of medications that promise greater effectiveness and fewer side effects. The new treatments could include steroids that fight leukemia or suppress the inflammation associated with autoimmune disorders without affecting metabolism or bone strength. Small molecules like SJ-AK might aid efforts to develop medicines to control the rapid, life-threatening over-production of a thyroid hormone known as thyroid storm. Guy said the thyroid hormone pathway is also being studied for new opportunities to better regulate obesity or metabolic disease related to cholesterol, triglycerides and fatty acids.

For this study, researchers compared the activity of SJ-AK and NH-3. The compounds use different techniques to target distinct spots in a thyroid hormone signaling pathway.

NH-3 works by competing with a thyroid hormone to bind to the receptor in the cell nucleus. If the hormone wins the competition, the binding starts a biochemical cascade that regulates the activity of genes in the pathway. Those genes produce the proteins that affect growth and other key biological processes. If NH-3 binds to the receptor instead, the impact is like flipping the switch that cuts electricity to the entire building. The entire pathway remains dormant, which is not always desirable.

SJ-AK was developed in Guy’s laboratory. Rather than binding to the hormone receptor like NH-3 does, SJ-AK targets the next step in the pathway. SJ-AK works by displacing proteins called coactivators. Coactivator proteins normally bind to a pocket that is created when a thyroid hormone and receptor bind. As a result, SJ-AK functions like a circuit breaker, selectively blocking parts of the hormone signaling pathway.

In this study, researchers showed that while NH-3 and SJ-AK both target the same signaling pathway and some of the same genes, SJ-AK affects far fewer genes. In laboratory screening tests, researchers found the activity of 193 genes was affected by thyroid hormone. The genes included 79 whose activity was affected by NH-3 and 28 affected by SJ-AK. Investigators showed NH-3 and SJ-AK had little impact on genes outside the thyroid hormone pathways.

Scientists showed NH-3 and SJ-AK also altered the activity of cells. Growth hormone secretion increased 50 percent following the addition of thyroid hormone to human cells growing in the laboratory. When SJ-AK was added, the secretion of growth hormone fell. In another laboratory experiment, researchers reported that both NH-3 and SJ-AK blocked the cell proliferation triggered by growth hormone secretion.

Other authors are Jong Yeon Hwang and Ramy Attia, both formerly of St. Jude; Geoffrey Neale, of St. Jude; and Leggy Arnold of the University of Wisconsin at Milwaukee.

This research was funded in part by the National Institutes of Health and ALSAC.

St. Jude Children’s Research Hospital
St. Jude Children’s Research Hospital is internationally recognized for its pioneering research and treatment of children with cancer and other life-threatening diseases. The hospital’s research has helped push overall survival rates for childhood cancer from less than 20 percent when the institution opened to almost 80 percent today. It is the first and only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children, and no family ever pays St. Jude for care. For more information, visit www.stjude.org.
St. Jude Public Relations Contacts:
Summer Freeman
(desk) 901-595-3061
(cell) 901-297-9861
summer.freeman@stjude.org
Carrie Strehlau
(desk) 901-595-2295
(cell) 901-297-9875
carrie.strehlau@stjude.org

Summer Freeman | Newswise Science News
Further information:
http://www.stjude.org

More articles from Life Sciences:

nachricht Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz

nachricht Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Fighting drug resistant tuberculosis – InfectoGnostics meets MYCO-NET² partners in Peru

28.04.2017 | Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

 
Latest News

Wireless power can drive tiny electronic devices in the GI tract

28.04.2017 | Medical Engineering

Ice cave in Transylvania yields window into region's past

28.04.2017 | Earth Sciences

Nose2Brain – Better Therapy for Multiple Sclerosis

28.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>