Discovery and SAR of Natural-Product-Inspired RXR Agonists with Heterodimer Selectivity to PPARδ‐RXR
Discovery and SAR of Natural-Product-Inspired RXR Agonists with Heterodimer Selectivity to PPARδ‐RXR
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天然产物启发的 RXR 激动剂的发现和 SAR，对 PPARδ-RXR 具有异二聚体选择性
DOI：
10.1021/acschembio.0c00146
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发表时间：
2020
影响因子：
4
通讯作者：
and Makoto Inoue
中科院分区：
文献类型：
--
作者：
Ken-ichi Nakashima;Eiji Yamaguchi;Chihaya Noritake;Yukari Mitsugi;Mayuki Goto;Takao Hirai;Naohito Abe;Eiji Sakai;Masayoshi Oyama;Akichika Itoh;and Makoto Inoue
一种已知的天然产物 magnogenic B，被鉴定为类视黄醇 X 受体 (RXR) α 的激动剂。 Magn醛 B 从木兰科 (Magnolia obovata) 中分离出来，并与更有效的类似物一起合成，用于筛选其 RXRα 激动活性。 Magn醛 B 的结构优化导致候选分子的开发，其效力提高了 440 倍。受体-配体对接模拟表明，在本研究中合成的类似物中，该分子与RXRα配体结合域具有最高的亲和力。此外，在使用 PPAR 响应元件驱动报告基因 (PPRE-Luc) 的荧光素酶报告基因测定中，选择性激活过氧化物酶体增殖物激活受体 (PPAR) δ-RXR 异二聚体，其功效比 PPARα-RXR 和 PPARγ-RXR 更强。该分子的 PPARδ 活性被 RXR 和 PPARδ 拮抗剂显着抑制，而 GW501516 的活性不受 RXR 拮抗剂影响。此外，该分子在使用 Gal4 混合系统的报告基因测定中表现出特别弱的 PPARδ 激动活性。因此，获得的数据表明，优化分子的弱 PPARδ 激动活性通过其自身的 RXR 激动活性协同增强，表明 PPARδ-RXR 异二聚体具有有效的激动活性。
A known natural product, magnaldehyde B, was identified as an agonist of retinoid X receptor (RXR) α. Magnaldehyde B was isolated fromMagnolia obovata(Magnoliaceae) and synthesized along with more potent analogs for screening of their RXRα agonistic activities. Structural optimization of magnaldehyde B resulted in the development of a candidate molecule that displayed a 440-fold increase in potency. Receptor–ligand docking simulations indicated that this molecule has the highest affinity with the ligand binding domain of RXRα among the analogs synthesized in this study. Furthermore, the selective activation of the peroxisome proliferator-activated receptor (PPAR) δ-RXR heterodimer with a stronger efficacy compared to those of PPARα-RXR and PPARγ-RXR was achieved in luciferase reporter assays using the PPAR response element driven reporter (PPRE-Luc). The PPARδ activity of the molecule was significantly inhibited by the antagonists of both RXR and PPARδ, whereas the activity of GW501516 was not affected by the RXR antagonist. Furthermore, the molecule exhibited a particularly weak PPARδ agonistic activity in reporter gene assays using the Gal4 hybrid system. The obtained data therefore suggest that the weak PPARδ agonistic activity of the optimized molecule is synergistically enhanced by its own RXR agonistic activity, indicating the potent agonistic activity of the PPARδ-RXR heterodimer.