Discovery of a “Gatekeeper” Antagonist that Blocks Entry Pathway to Retinoid X Receptors (RXRs) without Allosteric Ligand Inhibition in Permissive RXR Heterodimers,Journal of Medicinal Chemistry

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Discovery of a “Gatekeeper” Antagonist that Blocks Entry Pathway to Retinoid X Receptors (RXRs) without Allosteric Ligand Inhibition in Permissive RXR Heterodimers
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-24 , DOI: 10.1021/acs.jmedchem.0c01354
Masaki Watanabe ₁ , Michiko Fujihara _{1,

2} , Tomoharu Motoyama ₃ , Mayu Kawasaki ₃ , Shoya Yamada _{1,

4} , Yuta Takamura ₁ , Sohei Ito ₃ , Makoto Makishima ₅ , Shogo Nakano ₃ , Hiroki Kakuta ₁

Affiliation

Retinoid X receptor (RXR) heterodimers such as PPAR/RXR, LXR/RXR, and FXR/RXR can be activated by RXR agonists alone and are therefore designated as permissive. Similarly, existing RXR antagonists show allosteric antagonism toward partner receptor agonists in these permissive RXR heterodimers. Here, we show 1-(3-(2-ethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylic acid (14, CBTF-EE) as the first RXR antagonist that does not show allosteric inhibition in permissive RXR heterodimers. This compound was designed based on the hypothesis that RXR antagonists that do not induce conformational changes of RXR would not exhibit such allosteric inhibition. CD spectra and X-ray co-crystallography of the complex of 14 and the RXR ligand binding domain (LBD) confirmed that 14 does not change the conformation of hRXR-LBD. The X-ray structure analysis revealed that 14 binds at the entrance of the ligand binding pocket (LBP), blocking access to the LBP and thus serving as a “gatekeeper”.

中文翻译：

发现了一种“ Gatekeeper”拮抗剂，该拮抗剂阻断了允许的RXR异源二聚体在没有变构配体抑制的情况下进入类维生素A X受体（RXR）的进入途径

类视黄醇X受体（RXR）异二聚体（例如PPAR / RXR，LXR / RXR和FXR / RXR）可以单独由RXR激动剂激活，因此被指定为允许的。同样，现有的RXR拮抗剂在这些允许的RXR异二聚体中对伴侣受体激动剂表现出变构拮抗作用。在这里，我们显示了1-（3-（2-乙氧基乙氧基）-5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基）-2-（三氟甲基）-1 H-苯并[ d ]咪唑-5-羧酸（14（CBTF-EE）作为第一个在允许的RXR异二聚体中不显示变构抑制作用的RXR拮抗剂。该化合物是基于以下假设设计的：不诱导RXR构象变化的RXR拮抗剂不会表现出这种变构抑制作用。14和RXR配体结合域（LBD）的复合物的CD光谱和X射线共晶体学证实，14不会改变hRXR-LBD的构象。X射线结构分析显示，14个分子在配体结合袋（LBP）的入口处结合，从而阻止了对LBP的进入，从而充当了“守门人”。

更新日期：2021-01-14

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