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.
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We thank N. Nedelsky for editorial assistance. We thank the transgenic core facility at St. Jude for production of AR121Q transgenic mice and ARC Technical Services at St. Jude for surgical and animal care assistance. We also thank W. Denney for guidance in use of the 'PKNCA' R package. This work was supported by the Howard Hughes Medical Institute (J.P.T.), the American-Lebanese-Syrian Associated Charities (J.P.T., H.T.), NIH R01 NS053825 (J.P.T.), NIH R01 NS100023 (A.R.L.), the Muscular Dystrophy Association (A.R.L.) and the Kennedy's Disease Association (H.C.M.).
The authors declare no competing financial interests.
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Badders, N., Korff, A., Miranda, H. et al. Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy. Nat Med 24, 427–437 (2018). https://doi.org/10.1038/nm.4500