Nature medicine · 2018
Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
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Badders Nisha M, Korff Ane, Miranda Helen C, Vuppala Pradeep K, Smith Rebecca B, Winborn Brett J, Quemin Emmanuelle R, Sopher Bryce L, Dearman Jennifer, Messing James, Kim Nam Chul, Moore Jennifer, Freibaum Brian D, Kanagaraj Anderson P, Fan Baochang, Tillman Heather, Chen Ping-Chung, Wang Yingzhe, Freeman Burgess B, Li Yimei, Kim Hong Joo, La Spada Albert R, Taylor J Paul
Аннотация
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.