Discovery of structural determinants enabling RXR subtype selectivity and design of selective RXR ligands

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The proposed project shall study the potential of individual targeting of the three subtypes of the human nuclear retinoid X receptor (RXR) with subtype-selective drug-like small molecule ligands. RXR has pharmacological relevance in cancer therapy as molecular target of the drug Bexarotene, which, however, activates all RXR subtypes (RXR alpha, RXR beta, RXR gamma) with similar potency. RXRs are involved in many physiological and pathophysiological processes and essential for cellular homeostasis. Thus, every cell with a nucleus expresses at least one RXR subtype. pan-RXR agonism as it is exhibited by known RXR ligands has considerable potential for side-effects and the pan-RXR agonistic drug Bexarotene e.g. causes elevated triglyceride levels and hypothyroidism as severe adverse activities. Due to the varying expression pattern of the three RXR subtypes in different organs and tissues, subtype-selective RXR modulators hold potential to provide therapeutic efficacy with reduced adverse effects.Recently, we have discovered the natural product valerenic acid as first-in-class subtype-selective RXR agonist which confirmed that the three RXR subtypes can be selectively modulated with subtype-selective small molecule ligands despite their enormous structural homology. Aim of the present project is the evaluation of structural requirements of RXR ligands that enable subtype-selective modulation of RXR alpha, RXR beta and RXR gamma. All knowledge obtained from this analysis shall then be combined and applied to the design of such subtype-selective RXR ligands as pharmacological tools to study the individual therapeutic potential of the three RXR subtypes.For this, the structure activity relationship of valerenic acid, the first-in-class subtype-selective RXR modulator, shall be systematically studied and derivatives of the natural product with subtype-selectivity and improved potency shall be developed. Knowledge obtained from these studies shall then be applied to synthetically less demanding RXR modulator classes. This endeavor will be supported by co-crystal structure analyses which we have already initiated. In addition to the subtype-selective RXR ligand valerenic acid, our co-crystal structure data provide hypotheses for subtype-selective RXR modulator development, as well. On one hand, our studies indicate a structural difference in the RXR alpha and RXR beta ligand binding sites concerning the position of an Asn residue (RXR alpha-Asn306). On the other hand, a cysteine residue (RXR alpha-Cys432) is present in the binding sites of all RXRs that enables the design of covalent RXR ligands. Both regions are accessible to RXR ligands and shall be studied for their potential to drive subtype-selectivity with specifically designed ligands.