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Research involving thyroid hormone lays foundation for more targeted drug development
Date:10/21/2011

ted 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
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Contact: Summer Freeman
summer.freeman@stjude.org
901-595-3061
St. Jude Children's Research Hospital
Source:Eurekalert

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