ArticleThe Journal of biological chemistry2011
Methylsulfonylnitrobenzoates, a new class of irreversible inhibitors of the interaction of the thyroid hormone receptor and its obligate coactivators that functionally antagonizes thyroid hormone.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 32 citations in OpenAlex.
- Receptor modulators associated with the hypothalamus -pituitary-thyroid axis.Frontiers in pharmacology · 2023Review
- Deficiency of thyroid hormone receptor protects retinal pigment epithelium and photoreceptors from cell death in a mouse model of age-related macular degeneration.Cell death & disease · 2022Article
- Allosteric Binding Sites On Nuclear Receptors: Focus On Drug Efficacy and Selectivity.International journal of molecular sciences · 2020Article
- Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Article
- Prediction of binding affinity and efficacy of thyroid hormone receptor ligands using QSAR and structure-based modeling methods.Toxicology and applied pharmacology · 2014Article
- Structure of human RNA N⁶-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation.Nucleic acids research · 2014Article
- Peroxisome proliferation-activated receptor δ agonist GW0742 interacts weakly with multiple nuclear receptors, including the vitamin D receptor.Biochemistry · 2013Article
- Synthesis and evaluation of methylsulfonylnitrobenzamides (MSNBAs) as inhibitors of the thyroid hormone receptor-coactivator interaction.Bioorganic & medicinal chemistry letters · 2013Article
- Discovery of the first irreversible small molecule inhibitors of the interaction between the vitamin D receptor and coactivators.Journal of medicinal chemistry · 2012Article
- Synthesis and evaluation of sulfonylnitrophenylthiazoles (SNPTs) as thyroid hormone receptor-coactivator interaction inhibitors.Journal of medicinal chemistry · 2012Article
- "True" antiandrogens-selective non-ligand-binding pocket disruptors of androgen receptor-coactivator interactions: novel tools for prostate cancer.Journal of medicinal chemistry · 2012Article
- On the mechanism of action of SJ-172550 in inhibiting the interaction of MDM4 and p53.PloS one · 2012Article
- A quantitative high-throughput screen identifies novel inhibitors of the interaction of thyroid receptor beta with a peptide of steroid receptor coactivator 2.Journal of biomolecular screening · 2011Article
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor (NR) superfamily and regulate development, growth, and metabolism. Upon binding thyroid hormone, TR undergoes a conformational change that allows the release of corepressors and the recruitment of coactivators, which in turn regulate target gene transcription. Although a number of TR antagonists have been developed, most are analogs of the endogenous hormone that inhibit ligand binding. In a screen for inhibitors that block the association of TRβ with steroid receptor coactivator 2 (SRC2), we identified a novel methylsulfonylnitrobenzoate (MSNB)-containing series that blocks this interaction at micromolar concentrations. Here we have studied a series of MSNB analogs and characterized their structure activity relationships. MSNB members do not displace thyroid hormone T3 but instead act by direct displacement of SRC2. MSNB series members are selective for the TR over the androgen, vitamin D, and PPARγ NR members, and they antagonize thyroid hormone-activated transcription action in cells. The methylsulfonylnitro group is essential for TRβ antagonism. Side-chain alkylamine substituents showed better inhibitory activity than arylamine substituents. Mass spectrum analysis suggested that MSNB inhibitors bind irreversibly to Cys-298 within the AF-2 cleft of TRβ to disrupt SRC2 association.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.