51. Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy
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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, III, Burgess B Freeman, Li, Yimei, Kim, Hong Joo, La Spada, Albert R, and Taylor, J Paul
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Biological response modifiers -- Physiological aspects -- Health aspects ,Kennedy disease -- Development and progression -- Genetic aspects -- Care and treatment ,Hormone receptors -- Genetic aspects -- Health aspects ,Muscular atrophy -- Analysis -- Physiological aspects -- Care and treatment ,Androgens -- Physiological aspects -- Health aspects ,Biological sciences ,Health - Abstract
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., Author(s): Nisha M Badders [1]; Ane Korff [1, 2]; Helen C Miranda [3]; Pradeep K Vuppala [4]; Rebecca B Smith [1]; Brett J Winborn [1]; Emmanuelle R Quemin [1]; Bryce [...]
- Published
- 2018
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