Issue Date: August 18, 2008
Small Molecule Rescues Mutant Hormone Receptor
Chemical rescue—a procedure in which a small molecule boosts the bioactivity of an impaired protein—has been used to restore function to a mutant thyroid hormone receptor associated with two diseases (Angew. Chem. Int. Ed., DOI: 10.1002/anie.200801742). The receptor, TRβ, plays a role in cell differentiation and maintenance. But a nonfunctioning mutated version, TRβ(H435Y), is associated with cancer and resistance to thyroid hormone (RTH). A. Quamrul Hassan (now an MIT postdoc) and John T. Koh at the University of Delaware speculated that a small molecule might tweak the mutant receptor’s hydrogen-bonding system and thus restore its function. By screening pyridine analogs, they identified a compound they named QH13, which does that. In cells, QH13 restores TRβ(H435Y) to a level of activity similar to that of TRβ in the presence of its natural ligand, triiodothyronine, and it binds much more selectively to TRβ(H435Y) than triiodothyronine does to TRβ. Koh and coworkers hope QH13 will help reveal the role of mutant thyroid hormone receptors in cancer initiation and progression and note that the small molecule could lead to anticancer and anti-RTH therapeutics.
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