Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by toxic gain of function of the androgen receptor (AR). Previously, we found that co-regulator binding through the activation function-2 (AF2) domain of AR is essential for pathogenesis, suggesting that AF2 may be a potential drug target for selective modulation of toxic AR activity. We screened previously identified AF2 modulators for their ability to rescue toxicity in a Drosophila model of SBMA. We identified two compounds, tolfenamic acid (TA) and 1-[2-(4-methylphenoxy)ethyl]-2-[(2-phenoxyethyl)sulfanyl]-1H-benzimidazole (MEPB), as top candidates for rescuing lethality, locomotor function and neuromuscular junction defects in SBMA flies. Pharmacokinetic analyses in mice revealed a more favorable bioavailability and tissue retention of MEPB compared with TA in muscle, brain and spinal cord. In a preclinical trial in a new mouse model of SBMA, MEPB treatment yielded a dose-dependent rescue from loss of body weight, rotarod activity and grip strength. In addition, MEPB ameliorated neuronal loss, neurogenic atrophy and testicular atrophy, validating AF2 modulation as a potent androgen-sparing strategy for SBMA therapy.

中文翻译：

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雄激素受体 AF2 结构域的选择性调节可挽救脊髓延髓性肌萎缩症的退化。


脊髓延髓肌萎缩症 (SBMA) 是一种由雄激素受体 (AR) 功能毒性增强引起的运动神经元疾病。此前，我们发现通过 AR 的激活功能 2 (AF2) 结构域结合的协同调节因子对于发病机制至关重要，这表明 AF2 可能是选择性调节有毒 AR 活性的潜在药物靶点。我们筛选了先前确定的 AF2 调节剂在 SBMA 果蝇模型中解救毒性的能力。我们确定了两种化合物，托芬那酸 (TA) 和 1-[2-(4-甲基苯氧基)乙基]-2-[(2-苯氧基乙基)硫基]-1H-苯并咪唑 (MEPB)，作为挽救致命性、运动能力的最佳候选化合物。 SBMA 果蝇的功能和神经肌肉接头缺陷。小鼠药代动力学分析表明，与 TA 相比，MEPB 在肌肉、大脑和脊髓中具有更有利的生物利用度和组织保留。在新的 SBMA 小鼠模型的临床前试验中，MEPB 治疗对体重、旋转杆活动和握力的减轻产生了剂量依赖性的缓解作用。此外，MEPB 改善了神经元损失、神经源性萎缩和睾丸萎缩，验证了 AF2 调节作为 SBMA 治疗的有效雄激素节约策略。