The Antagonists But Not Partial Agonists of Glucocorticoid Receptor Ligands Show Substantial Side Effect Dissociation
The Antagonists But Not Partial Agonists of Glucocorticoid Receptor Ligands Show Substantial Side Effect Dissociation
复制标题
DOI：
10.1210/en.2010-1447
复制
发表时间：
2011-08-01
期刊：
影响因子：
4.8
通讯作者：
Obukowicz, Mark G.
中科院分区：
文献类型：
--
作者：
Hu, Xiao;Du, Sarah;Obukowicz, Mark G.
具有糖皮质激素功效但没有伴随的副作用的合成糖皮质激素受体（GR）配体将满足治疗炎性疾病的未满足的医学需求。据推测，以不同于激动剂和拮抗剂的方式移动螺旋12的GR配体将赋予不同的GR构象，从而导致差异基因表达，并最终使GR活性与副作用分离。将预期干扰螺旋12的结构特征并入非甾体三环支架中，以产生新型、高亲和力和选择性GR配体，其在细胞测定中表现出双重功能，部分但稳健的激动剂活性用于炎性细胞因子抑制，以及完全的拮抗剂活性用于报告基因激活。相反，不太可能阻碍螺旋12的类似物表现出报告基因激活的部分激动剂活性。在原代人前脂肪细胞、肝细胞和成骨细胞中证明了充分拮抗剂活性对大量副作用解离的要求，其中分别检查了对脂肪形成、参与骨形成的关键基因和对骨形成重要的基因的影响。解离的GR配体，尽管缺乏显着的报告基因激活，弱招募有限数量的共激活因子，如过氧化物酶体增殖物激活受体-γ共激活因子1 α。转录激活对过氧化物酶体增殖物激活受体-γ共激活因子1 α和GR水平敏感，为基因表达的细胞选择性调节提供了基础。在小鼠炎症模型中进一步证明了解离的配体的抗肿瘤活性。总之，这些结果表明，这些配体是有前途的候选人，具有强大的抗肿瘤活性和可能的解离对糖皮质激素诱导的副作用。（内分泌学152：3123-3134，2011）
A synthetic glucocorticoid receptor (GR) ligand with the efficacy of a glucocorticoid, but without the accompanying side effects, would meet an unmet medical need for the treatment of inflammatory diseases. It was hypothesized that a GR ligand that shifted helix 12 in a manner distinct from an agonist and an antagonist would confer a distinct GR conformation, resulting in differential gene expression and, ultimately, dissociation of antiinflammatory activity from side effects. A structural feature expected to interfere with helix 12 was incorporated into a nonsteroidal, tricyclic scaffold to create novel, high-affinity, and selective GR ligands that manifested a dual function in cellular assays, partial but robust agonist activity for inflammatory cytokine inhibition, and full antagonist activity for reporter gene activation. In contrast, analogs not likely to hinder helix 12 exhibited partial agonist activity for reporter gene activation. The requirement of full antagonist activity for substantial side effect dissociation was demonstrated in primary human preadipocytes, hepatocytes, and osteoblasts in which effects on adipogenesis, key genes involved in gluconeogenesis, and genes important for bone formation were examined, respectively. The dissociated GR ligands, despite lacking significant reporter gene activation, weakly recruit a limited number of coactivators such as peroxisomal proliferator-activated receptor-gamma coactivator 1 alpha. Transcriptional activation was sensitive to both peroxisomal proliferator-activated receptor-gamma coactivator 1 alpha and GR levels, providing a basis for cell-selective modulation of gene expression. The antiinflammatory activity of the dissociated ligands was further demonstrated in mouse models of inflammation. Together these results suggest that these ligands are promising candidates with robust antiinflammatory activity and likely dissociation against glucocorticoid-induced side effects. (Endocrinology 152: 3123-3134, 2011)