Dominguez Marta, Alvarez Susana, de Lera Angel R
Departamento de Química Orgánica, Facultade de Química, CINBIO and IBIV, Universidade de Vigo, Campus As Lagoas-Marcosende, 36310 Vigo, Spain.
Curr Top Med Chem. 2017;17(6):631-662. doi: 10.2174/1568026616666160617072521.
Retinoid X receptors (RXRs) are promiscuous partners of heterodimeric associations with other members of the Nuclear Receptor (NR) superfamily. Through these liaisons RXR ligands ("rexinoids") either transcriptionally activate on their own the "permissive" subclass of heterodimers (PPAR/RXR, LXR/RXR, FXR/RXR) or synergize with partner ligands in the "non-permissive" subclass of heterodimers (RAR/RXR, VDR/RXR and TR/RXR). The nature and extent of the interaction of the ligand-receptor complexes with co-regulators, which is cell and context-dependent, results ultimately in transcriptional modulation of cognate gene networks. RXR modulators hold therapeutical potential for the treatment of cancer and other diseases related to nutrient acquisition and disposal, among them metabolic diseases. A rexinoid (bexarotene) has indeed reached the clinic for the treatment of cutaneous T-cell lymphoma. The modulation of RXR function by rexinoids acting as agonists, parcial agonists, inverse agonists or antagonists is encoded in the structure of the ligandreceptor complexes. A very large number of rexinoids with a wide structural diversity has been published. In addition to natural products and other ligands discovered by HTS or mere serendipity, most rexinoids have been rationally designed based on the structures of existing complexes with RXR determined by X-Ray or based on Molecular Modeling. Although the structural rationale for the modulation of the ligand-receptor complexes is reasonably well understood, it has not yet been possible to predict the correlation between ligand structure and physiological response, particularly in the case of heterodimer-selective rexinoids.
维甲酸X受体（RXRs）是与核受体（NR）超家族其他成员形成异源二聚体的随意伙伴。通过这些联系，RXR配体（“类视黄醇”）要么自身转录激活异源二聚体的“许可”亚类（PPAR/RXR、LXR/RXR、FXR/RXR），要么在异源二聚体的“非许可”亚类（RAR/RXR、VDR/RXR和TR/RXR）中与伙伴配体协同作用。配体-受体复合物与共调节因子相互作用的性质和程度取决于细胞和环境，最终导致同源基因网络的转录调节。RXR调节剂在治疗癌症和其他与营养获取和代谢相关的疾病（包括代谢性疾病）方面具有治疗潜力。一种类视黄醇（贝沙罗汀）确实已进入临床用于治疗皮肤T细胞淋巴瘤。作为激动剂、部分激动剂、反向激动剂或拮抗剂的类视黄醇对RXR功能的调节编码在配体-受体复合物的结构中。已经发表了大量结构多样的类视黄醇。除了天然产物和通过高通量筛选或偶然发现的其他配体之外，大多数类视黄醇都是基于通过X射线确定的与RXR的现有复合物结构或基于分子建模进行合理设计的。尽管对配体-受体复合物调节的结构原理有相当好的理解，但尚未能够预测配体结构与生理反应之间的相关性，特别是在异源二聚体选择性类视黄醇的情况下。
