Rational Design and Synthesis of a Novel Thyroid Hormone Antagonist That Blocks Coactivator Recruitment

Abstract

Recent efforts have focused on the design and synthesis of thyroid hormone (T(3)) antagonists as potential therapeutic agents and chemical probes to understand hormone-signaling pathways. We previously reported the development of novel first-generation T(3) antagonists DIBRT, HY-4, and GC-14 using the "extension hypothesis" as a general guideline in hormone antagonist design.(1-3) These compounds contain extensions at the 5'-position (DIBRT, GC-14) of the outer thyronine ring or from the bridging carbon (HY-4). All of these compounds have only a modest affinity and potency for the thyroid hormone receptor (TR) that limits studies of their antagonistic actions. Here, we report the design and synthesis of a novel series of 5'-phenylethynyl derivatives sharing the GC-1 halogen-free thyronine scaffold.(4) One compound (NH-3) is a T(3) antagonist with negligible TR agonist activity and improved TR binding affinity and potency that allow for further characterization of its observed activity. One mechanism for antagonism appears to be the ability of NH-3 to block TR-coactivator interactions. NH-3 will be a useful pharmacological tool for further study of T(3) signaling and TR function.

Rapid nongenomic actions of thyroid hormone

“…T 3 , LY294002, and actinomycin D were purchased from EMD Biosciences (San Diego, CA). NH-3 was synthesized and dissolved in DMSO as described (32). Anti-TR antibody (sc-739 and sc-737) was purchased from Santa Cruz Biotechnology (Santa Cruz, CA), and anti-p85␣ antibody was from Upstate Biotechnology (Lake Placid, NY).…”

A Thyroid Hormone Antagonist That Inhibits Thyroid Hormone Action in Vivo

“…Chemicals-The synthesis and purification of NH-3 has been described in detail previously (9). Lyophilized NH-3 was reconstituted in 100% dimethyl sulfoxide (Me 2 SO) at a concentration of 10 mM and stored in aliquots at Ϫ20°C until use.…”

The history of a developmental stage: Metamorphosis in chordates

“…However, many other hypotheses can be proposed, since in vivo functional experiments are still to be completed. The use of specific TR agonists and antagonists (Chiellini et al, 1998;Lim et al, 2002;Nguyen et al, 2002) could help deciphering the specific role of TR in this inverted situation.…”