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

拟建项目将研究利用亚型选择性药物样小分子配体对人核类视黄醇X受体（RXR）的三种亚型进行个体化靶向的潜力。RXR作为药物Bexarotene的分子靶点在癌症治疗中具有药理意义，然而，Bexarotene以相似的效力激活所有RXR亚型（RXR α、RXR β、RXR γ）。RXRs参与许多生理和病理生理过程，对细胞稳态至关重要。因此，每个有细胞核的细胞至少表达一种RXR亚型。已知的RXR配体所表现出的泛RXR激动作用具有相当大的潜在副作用，例如，泛RXR激动作用药物贝沙罗汀会导致甘油三酯水平升高和甲状腺功能减退。由于三种RXR亚型在不同器官和组织中的表达模式不同，亚型选择性RXR调节剂具有降低不良反应的治疗效果的潜力。近年来，我们首次发现天然产物戊酸是一类亚型选择性RXR激动剂，这证实了三种RXR亚型尽管具有巨大的结构同源性，但可以被亚型选择性小分子配体选择性调节。本项目的目的是评估RXR配体的结构要求，使RXR α、RXR β和RXR γ的亚型选择性调制成为可能。然后将从该分析中获得的所有知识结合起来，并应用于设计这种亚型选择性RXR配体作为药理学工具，以研究三种RXR亚型的个体治疗潜力。为此，应系统研究同类首创的亚型选择性RXR调节剂戊酸的构效关系，并开发具有亚型选择性和提高效力的天然产物衍生物。从这些研究中获得的知识将随后应用于合成要求较低的RXR调制器类别。这一努力将得到我们已经开始的共晶结构分析的支持。除了亚型选择性RXR配体戊酸外，我们的共晶结构数据也为亚型选择性RXR调制器的开发提供了假设。一方面，我们的研究表明RXR α和RXR β配体结合位点在Asn残基（RXR α - asn306）的位置上存在结构差异。另一方面，半胱氨酸残基（RXR α - cys432）存在于所有RXR的结合位点，使设计共价RXR配体成为可能。这两个区域都可以被RXR配体进入，并且应该研究它们在特定设计的配体上驱动亚型选择性的潜力。

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.