Tuning RXR Modulators for PGC1α Recruitment,Journal of Medicinal Chemistry

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Tuning RXR Modulators for PGC1α Recruitment
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-11 , DOI: 10.1021/acs.jmedchem.4c01231
Felix Nawa ₁ , Minh Sai ₁ , Jan Vietor ₁ , Roman Schwarzenbach ₁ , Anesa Bitić ₁ , Sina Wolff ₁ , Niklas Ildefeld ₂ , Jörg Pabel ₁ , Thomas Wein ₁ , Julian A Marschner ₁ , Jan Heering ₃ , Daniel Merk ₁

Affiliation

The molecular activation mechanism of the nuclear retinoid X receptors (RXRs) crucially involves ligand-induced corepressor release and coactivator recruitment which mediate transcriptional repression or activation. The ability of RXR to bind diverse coactivators suggests that a coregulator-selective modulation by ligands may open an avenue to tissue- or gene-selective RXR activation. Here, we identified strong induction of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) binding to RXR by a synthetic agonist but not by the endogenous ligand 9-cis retinoic acid. Structure-guided diversification of this lead resulted in a set of three structurally related RXR agonists with different ability to promote PGC1α recruitment in cell-free and cellular context. These results demonstrate that selective modulation of coregulator recruitment to RXR can be achieved with molecular glues and potentially open new therapeutic opportunities by targeting the ligand-induced RXR-PGC1α interaction.

中文翻译：

调整 RXR 调制器以招募 PGC1α

核视黄醇 X 受体 (RXR) 的分子激活机制关键涉及配体诱导的辅阻遏物释放和共激活子招募，从而介导转录抑制或激活。 RXR 结合多种共激活剂的能力表明，配体的辅助调节剂选择性调节可能为组织或基因选择性 RXR 激活开辟一条途径。在这里，我们发现合成激动剂可强烈诱导过氧化物酶体增殖物激活受体 γ 共激活剂 1α (PGC1α) 与 RXR 结合，但内源配体 9-顺式视黄酸则不会。该先导化合物的结构引导多样化产生了一组三种结构相关的 RXR 激动剂，它们在无细胞和细胞环境中具有不同的促进 PGC1α 募集的能力。这些结果表明，可以通过分子胶实现对 RXR 的辅助调节因子募集的选择性调节，并通过靶向配体诱导的 RXR-PGC1α 相互作用潜在地开辟新的治疗机会。

更新日期：2024-09-11

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