Institut National de la Santé et de la Recherche Médicale, U1054, Montpellier, France.
Curr Top Med Chem. 2012;12(6):505-27. doi: 10.2174/156802612799436687.
Retinoic acid receptors (RARs) are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth, differentiation, survival and death. Due to their regulatory potential, these nuclear receptors (NRs) are major drug targets for a variety of pathologies, including cancer and metabolic diseases. A large amount of RAR- and RXR-selective ligands, ranging from (partial) agonists to antagonists and inverse agonists, have been designed and the corresponding structural and functional analyses have provided deep insight into the molecular basis of ligand action. Ligands regulate, via allosteric conformational changes, the ability of these NRs to interact with different sets of coregulators, which in turn recruit enzymatically active complexes/machineries. Here, we describe strategies in the design of selective RXR and RAR modulators and review the structural mechanisms by which the diverse pharmacological classes of compounds modulate receptor functions. Finally, we discuss the perspectives for retinoid- and rexinoid-based therapies.
视黄酸受体（RARs）是配体控制的转录因子，它们与视黄醇 X 受体（RXRs）形成异二聚体，以调节细胞生长、分化、存活和死亡。由于其调节潜力，这些核受体（NRs）是多种病理的主要药物靶点，包括癌症和代谢疾病。已经设计了大量的 RAR 和 RXR 选择性配体，从（部分）激动剂到拮抗剂和反向激动剂，并且相应的结构和功能分析提供了对配体作用的分子基础的深刻见解。配体通过变构构象变化调节这些 NR 与不同核心调节剂集的相互作用能力，而核心调节剂反过来募集具有酶活性的复合物/机械。在这里，我们描述了设计选择性 RXR 和 RAR 调节剂的策略，并综述了不同药理学类别的化合物调节受体功能的结构机制。最后，我们讨论了基于视黄酸和类视黄醇的治疗的前景。
