PDF(Pubmed)
Abstract：
All-trans retinoic acid (ATRA), the major active metabolite of all-trans retinol (vitamin A), is a key hormonal signaling molecule. In the adult organism, ATRA has a widespread influence on processes that are crucial to the growth and differentiation of cells and, in turn, the acquisition of mature cell functions. Therefore, there is considerable potential in the use of retinoids to treat diseases. ATRA binds to the retinoic acid receptors (RAR) which, as activated by ATRA, selectively regulate gene expression. There are three main RAR isoforms, RARα, RARβ, and RARγ. They each have a distinct role, for example, RARα and RARγ regulate myeloid progenitor cell differentiation and hematopoietic stem cell maintenance, respectively. Hence, targeting an isoform is crucial to developing retinoid-based therapeutics. In principle, this is exemplified when ATRA is used to treat acute promyelocytic leukemia (PML) and target RARα within PML-RARα oncogenic fusion protein. ATRA with arsenic trioxide has provided a cure for the once highly fatal leukemia. Recent in vitro and in vivo studies of RARγ have revealed the potential use of agonists and antagonists to treat diseases as diverse as cancer, heterotopic ossification, psoriasis, and acne. During the final drug development there may be a need to design newer compounds with added modifications to improve solubility, pharmacokinetics, or potency. At the same time, it is important to retain isotype specificity and activity. Examination of the molecular interactions between RARγ agonists and the ligand binding domain of RARγ has revealed aspects to ligand binding that are crucial to RARγ selectivity and compound activity and key to designing newer compounds.
摘要：
全反式维甲酸(ATRA),全反式视黄醇（维生素A）的主要活性代谢产物，是一个关键的激素信号分子。在成年生物体中，ATRA对细胞生长和分化至关重要的过程具有广泛的影响,反过来,获得成熟的细胞功能。因此,使用类维生素A治疗疾病有相当大的潜力。ATRA与视黄酸受体（RAR）结合，由ATRA激活，选择性调节基因表达。有三种主要的RAR亚型，RARα,RARβ,和RARγ。他们每个人都有不同的角色，例如,RARα和RARγ调节骨髓祖细胞分化和造血干细胞维持,分别。因此，靶向同工型对于开发基于类维生素A的疗法至关重要.原则上,当ATRA用于治疗急性早幼粒细胞白血病（PML）并靶向PML-RARα致癌融合蛋白中的RARα时，这就是例证。使用三氧化二砷的ATRA为曾经高度致命的白血病提供了治愈方法。最近对RARγ的体外和体内研究揭示了激动剂和拮抗剂治疗癌症等多种疾病的潜在用途。异位骨化,牛皮癣,和痤疮。在最终的药物开发过程中，可能需要设计具有增加修饰的新型化合物以提高溶解度。药代动力学，或效力。同时,重要的是保留同种型特异性和活性。对RARγ激动剂与RARγ的配体结合域之间的分子相互作用的检查揭示了配体结合的方面，这些方面对RARγ选择性和化合物活性至关重要，并且是设计新型化合物的关键。
