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.