Drug options for the life‐threatening Cushing's disease are limited, and surgical resection or radiation therapy is not invariably effective. Testicular receptor 4 (TR4) has been identified as a novel drug target to treat Cushing's disease. We built the structure model of TR4 and searched the TR4 antagonist candidate via in silico virtual screening. Bexarotene was identified as an antagonist of TR4 that can directly interact with TR4 ligand binding domain (TR4‐LBD) and induces a conformational change in the secondary structure of TR4‐LBD. Bexarotene suppressed AtT‐20 cell growth, proopiomelanocortin (POMC) expression and adrenocorticotropin (ACTH) secretion. Mechanism dissection revealed that bexarotene could suppress TR4‐increased POMC expression via promoting the TR4 translocation from the nucleus to the cytoplasm. This TR4 translocation might then result in reducing the TR4 binding to the TR4 response element (TR4RE) on the 5’ promoter region of POMC. Results from in vivo mouse model also revealed that oral bexarotene administration markedly suppressed ACTH‐secreting tumour growth, adrenal enlargement and the secretion of ACTH and corticosterone in mice with already established tumours. Together, these results suggest that bexarotene may be developed as a potential novel therapeutic drug to better suppress Cushing's disease.

中文翻译：

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用拮抗剂贝沙罗汀靶向 TR4 核受体可以抑制 AtT-20 细胞中的阿黑皮素原信号传导

危及生命的库欣病的药物选择有限，手术切除或放射治疗并非总是有效。睾丸受体 4 (TR4) 已被确定为治疗库欣病的新药物靶点。我们建立了TR4的结构模型，并通过计算机虚拟筛选搜索了TR4拮抗剂候选物。Bexarotene 被鉴定为 TR4 的拮抗剂，可直接与 TR4 配体结合域 (TR4-LBD) 相互作用并诱导 TR4-LBD 二级结构的构象变化。贝沙罗汀抑制 AtT-20 细胞生长、阿黑皮素原 (POMC) 表达和促肾上腺皮质激素 (ACTH) 分泌。机制解剖发现，蓓萨罗丁能够抑制TR4-增加POMC表达通过促进 TR4 从细胞核到细胞质的易位。这种 TR4 易位可能会导致 TR4 与 POMC 5' 启动子区域上的 TR4 响应元件 (TR4RE) 的结合减少。来自体内小鼠模型的结果还表明，口服贝沙罗汀给药显着抑制了已患有肿瘤的小鼠中分泌 ACTH 的肿瘤生长、肾上腺增大以及 ACTH 和皮质酮的分泌。总之，这些结果表明贝沙罗汀可能被开发为一种潜在的新型治疗药物，以更好地抑制库欣病。