Inhibitors of the Interaction of a Thyroid Hormone Receptor and Coactivators: Preliminary Structure−Activity Relationships

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, United States
Journal of Medicinal Chemistry (Impact Factor: 5.45). 12/2007; 50(22):5269-80. DOI: 10.1021/jm070556y
Source: PubMed


The modulation of gene regulation by blocking the interaction between the thyroid receptor (TR) and obligate coregulators has been reported recently with the discovery of the lead compound 3-(dimethylamino)-1-(4-hexylphenyl)propan-1-one). Herein we report studies aimed at optimization of this initial hit to determine the basic parameters of the structure-activity relationships and clarify the mechanism of action. These studies provided new insights, showing that activity and TRbeta isoform selectivity is highly correlated with the structural composition of these covalent inhibitors.

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Available from: Eva Estebanez-Perpiña
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    • "For the AF-2 domain, 210 ligands were found; however, only 181 had well-defined IC 50 values (Arnold et al., 2007b; Hwang et al., 2009, 2012) (see Table 2). The IC 50 values associated with inhibition of coregulatory peptide SRC2-2 binding to THRβ were determined using fluorescence polarization (Arnold et al., 2007b; Hwang et al., 2009, 2012). Collected IC 50 values varied from 0.0191 nM to 32 μM and from 0.310 μM to 100 μM for LBD and AF-2 domains, respectively. "
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    • "Several lines of evidence support the idea that AR AF2 pocket can be a bona fide 67 pharmaceutical target (Arnold et al. 2005, 2006, 2007; Estébanez-Perpiñá and 68 Fletterick 2007; Chang and McDonnell 2005). Small molecules have been reported 69 to bind weakly to AR AF2 by Xray crystallography and fluorescent polarization 70 assays (Estébanez-Perpiñá et al. 2007a). "
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