Methylsulfonylnitrobenzoates, a new class of irreversible inhibitors of the interaction of the thyroid hormone receptor and its obligate coactivators that functionally antagonizes thyroid hormone. J Biol Chem 2011 Apr 08;286(14):11895-908
Date
02/16/2011Pubmed ID
21321127Pubmed Central ID
PMC3069392DOI
10.1074/jbc.M110.200436Scopus ID
2-s2.0-79953303428 (requires institutional sign-in at Scopus site) 33 CitationsAbstract
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.
Author List
Hwang JY, Huang W, Arnold LA, Huang R, Attia RR, Connelly M, Wichterman J, Zhu F, Augustinaite I, Austin CP, Inglese J, Johnson RL, Guy RKAuthor
Alexander (Leggy) Arnold PhD Professor in the Chemistry & Biochemistry department at University of Wisconsin - MilwaukeeMESH terms used to index this publication - Major topics in bold
Aniline CompoundsHEK293 Cells
Hep G2 Cells
Humans
Methylamines
Nitrobenzoates
Nuclear Receptor Coactivator 2
Piperidines
Protein Binding
Receptors, Thyroid Hormone
Reverse Transcriptase Polymerase Chain Reaction
Structure-Activity Relationship
