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

发现实现 RXR 亚型选择性的结构决定因素和选择性 RXR 配体的设计

• 批准号: 432406391
• 负责人: Professor Dr. Daniel Merk
• 金额: --
• 依托单位: Lehrstuhl für Pharmazeutische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/432406391?language=en
• 关键词: Discovery; structural; determinants; enabling; RXR

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.

拟开展的项目将研究用亚型选择性药物样小分子配体单独靶向人核维甲酸X受体（RXR）的三种亚型的潜力。RXR作为药物贝沙罗汀的分子靶标在癌症治疗中具有药理学相关性，然而，贝沙罗汀以相似的效力激活所有RXR亚型（RXR α、RXR β、RXR γ）。RXR参与许多生理和病理生理过程，对细胞稳态至关重要。因此，每一个有细胞核的细胞都表达至少一种RXR亚型。已知的RXR配体所表现的泛RXR激动作用具有相当大的副作用潜力，泛RXR激动药物贝沙罗汀（Bexarotene）例如引起甘油三酯水平升高和甲状腺功能减退，这是严重的副作用。由于三种RXR亚型在不同器官和组织中的不同表达模式，亚型选择性RXR调节剂具有提供具有降低的不良反应的治疗功效的潜力。我们已经发现天然产物缬草酸作为第一类亚型选择性RXR激动剂，其证实了三种RXR亚型可以用亚型-选择性的小分子配体，尽管它们具有巨大的结构同源性。本项目的目的是评估RXR配体的结构要求，这些配体能够对RXR α、RXR β和RXR γ进行亚型选择性调节。从该分析中获得的所有知识将被组合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，缬草酸，第一种亚型选择性RXR调节剂，应进行系统研究，并开发具有亚型选择性和改进效力的天然产物衍生物。从这些研究中获得的知识应应用于合成要求较低的RXR调制剂类别。这一奋进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配体缬草酸之外，我们的共晶结构数据也为亚型选择性RXR调节剂的开发提供了假设。一方面，我们的研究表明RXR α和RXR β配体结合位点在Asn残基位置（RXR α-Asn 306）方面存在结构差异。另一方面，半胱氨酸残基（RXR α-Cys 432）存在于所有RXR的结合位点中，这使得能够设计共价RXR配体。这两个区域都是RXR配体可及的，应研究它们用专门设计的配体驱动亚型选择性的潜力。