title: Binding characterization, synthesis and biological evaluation of RXRα antagonists targeting the coactivator binding site.
abstract: Previously we identified the first retinoid X receptor-alpha (RXRα) modulators that regulate the RXRα biological function via binding to the coregulator-binding site. Here we report the characterization of the interactions between the hit molecule and RXRα through computational modeling, mutagenesis, SAR and biological evaluation. In addition, we reported studies of additional new compounds and identified a molecule that mediated the NF-κB pathway by inhibiting the TNFα-induced IκBα degradation and p65 nuclear translocation.
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Dingyu
authors.initials: D
authors.lastname: Xu
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Shangjie
authors.initials: S
authors.lastname: Guo
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Ziwen
authors.initials: Z
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Bao
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Fengyu
authors.initials: F
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Xindao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhou
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, China; Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, China; Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: ysu@sbpdiscovery.org.
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
mesh_terms: D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D047490:Retinoid X Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
chemical_list: D001578:Benzopyrans; D008024:Ligands; D016328:NF-kappa B; D047490:Retinoid X Receptor alpha; D014212:Tretinoin
keywords: Coactivator-binding site ligand; Coregulator-binding site; Nuclear receptors; RXRα modulators; TNFα/NF-κB pathway