Similarities and Differences between Two Modes of Antagonism of the Thyroid Hormone Receptor

Abstract

Thyroid hormone (T3) mediates diverse physiological functions including growth, differentiation, and energy homeostasis through the thyroid hormone receptors (TR). The TR bind DNA at specific recognition sequences in the promoter regions of their target genes known as the thyroid hormone response elements (TREs). Gene expression at TREs regulated by TRs is mediated by coregulator recruitment to the DNA bound receptor. This TR-coregulator interaction controls transcription of target genes by multiple mechanisms including covalent histone modifications and chromatin remodeling. Our previous studies identified a β-aminoketone as a potent inhibitor of the TR-coactivator interaction. We describe here the activity of one of these inhibitors in modulating effects of T3 signaling in comparison to an established ligand-competitive inhibitor of TR, NH-3. The β-aminoketone was found to reverse thyroid hormone induced gene expression by inhibiting coactivator recruitment at target gene promoters, thereby regulating downstream effects of thyroid hormone. While mimicking the downstream effects of a ligand competitive inhibitor at the molecular level, the β-aminoketone affects only a subset of the thyroid responsive signaling network. Thus antagonists directed to the coregulator binding site have distinct pharmacological properties relative to ligand based antagonists and may provide complementary activity in vivo.

Similarities and Distinctions in Actions of Surface-Directed and Classic Androgen Receptor Antagonists

“…Our results differ from a previous comparison of a classic thyroid hormone (TH) receptor (TR) antagonist (NH-3) and a compound that blocks TR activity via covalent attachment to TR AF-2 (SJ-AK) [ 38 ]. Here, both compounds inhibited a range of TH responses.…”

Synthesis and Evaluation of Sulfonylnitrophenylthiazoles (SNPTs) as Thyroid Hormone Receptor–Coactivator Interaction Inhibitors

“…30, 35 Cells were co-treated with T3 (100 nM) and compound (10 μM). Controls included NH3, a ligand antagonist of T3, and a representative MSNB ( 1 ), a known T3 antagonist.…”

Thyroid Toxicogenomics

“…In fact, not only are these changes reflected but by comparing a THR-T3 inhibitor to a TRH-CoR inhibitor, Sadana et al found that these affect different subsets of T3 target genes in the human liver cell line HepG2 [125].…”