Discovery of structural determinants enabling RXR subtype selectivity and design of selective RXR ligands
Final Report Abstract
Pharmacological activation of the nuclear retinoid X receptors (RXR) holds therapeutic promise in neurodegeneration, cancer, and metabolic diseases. However, the wide distribution in all tissues and numerous roles of RXR as transcriptional regulator and universal nuclear receptor heterodimer partner require selective modulation for safe therapeutic application. Available RXR agonists like bexarotene fully activate all RXRs (RXRα, RXRβ, RXRγ) and various RXR heterodimers while molecular determinants enabling subtype and dimer preferential activity were elusive. The exceptional identity of the ligand binding pockets (LBP) of the three RXR subtypes presents a major challenge to the development of ligands with subtype preference but our previous discovery of the natural product valerenic acid as functionally selective RXRβ agonist demonstrated that such ligands can be obtained. Here, we approached subtype preferential RXR ligand development from several angles. We solved the first set of co-crystal structures of the three RXRs in complex with the same ligand as instrumental basis for structure-based design. We explored the structure-activity relationship of valerenic acid and identified structural features important for the natural product's unique activity on RXR as well as an analogue with improved selective RXR homodimer agonism. Knowledge transfer to synthetic RXR ligand scaffolds by structural fusion enabled the development of the first set of three single-subtype preferential RXR agonists as well as a highly potent and selective pan-RXR agonist chemical probe. These RXR modulators are very valuable tools for our future work on RXR and for the scientific community. Structural comparison of the RXR LBDs suggested potential for further avenues to subtype preferential interactions in sub-pockets close to Asn306 and Cys432, respectively (RXRα). Structure-guided design of ligands addressing these regions enabled significant improvement of RXRα preference offering further access to valuable next-generation chemical tools for RXR.
Publications
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Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms. International Journal of Molecular Sciences, 21(22), 8457.
Chaikuad, Apirat; Pollinger, Julius; Rühl, Michael; Ni, Xiaomin; Kilu, Whitney; Heering, Jan & Merk, Daniel
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Oxaprozin Analogues as Selective RXR Agonists with Superior Properties and Pharmacokinetics. Journal of Medicinal Chemistry, 64(8), 5123-5136.
Schierle, Simone; Chaikuad, Apirat; Lillich, Felix F.; Ni, Xiaomin; Woltersdorf, Stefano; Schallmayer, Espen; Renelt, Beatrice; Ronchetti, Riccardo; Knapp, Stefan; Proschak, Ewgenij & Merk, Daniel
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Rational Design of a New RXR Agonist Scaffold Enabling Single-Subtype Preference for RXRα, RXRβ, and RXRγ. Journal of Medicinal Chemistry, 66(1), 333-344.
Adouvi, Gustave; Isigkeit, Laura; López-García, Úrsula; Chaikuad, Apirat; Marschner, Julian A.; Schubert-Zsilavecz, Manfred & Merk, Daniel
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Structural Fusion of Natural and Synthetic Ligand Features Boosts RXR Agonist Potency. Journal of Medicinal Chemistry, 66(24), 16762-16771.
Adouvi, Gustave; Nawa, Felix; Ballarotto, Marco; Rüger, Lorena Andrea; Knümann, Loris; Kasch, Till; Arifi, Silvia; Schubert-Zsilavecz, Manfred; Willems, Sabine; Marschner, Julian A.; Pabel, Jörg & Merk, Daniel
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Structural Modification of the Natural Product Valerenic Acid Tunes RXR Homodimer Agonism. ChemMedChem, 18(21).
Zaienne, Daniel; Isigkeit, Laura; Marschner, Julian A.; Duensing‐Kropp, Silke; Höfner, Georg & Merk, Daniel
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Rational design and virtual screening identify mimetics of the RXR agonist valerenic acid. ChemMedChem, 19(5).
Isigkeit, Laura; Kärcher, Annette; Adouvi, Gustave; Arifi, Silvia & Merk, Daniel
