Spinal bulbar muscular atrophy (SBMA) results from a polyglutamine expansion in the androgen receptor (AR). Recently, co-regulator binding through the activation function 2 (AF2) domain of the AR has been indicated as essential for pathogenesis. Here, Badders and colleagues screened a panel of small molecules that had previously been identified as modulating co-regulator binding to the AR AF2 domain, which revealed that 1-[2-(4-methylphenoxy)ethyl]-2-[(2-phenoxyethyl)sulfanyl]-1H-benzimidazole (MEPB) was able to rescue toxicity in a Drosophila SBMA model. In a preclinical trial in SBMA mice, intraperitoneal MEPB treatment augmented body weight, rotarod activity and grip strength, improved gait and hindlimb clasping and ameliorated neurogenic atrophy, neuronal loss and testicular atrophy.
References
Badders, N. M. et al. Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy. Nat. Med. https://doi.org/10.1038/nm.4500 (2018)
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Crunkhorn, S. New strategy for SBMA therapy. Nat Rev Drug Discov 17, 316 (2018). https://doi.org/10.1038/nrd.2018.55
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DOI: https://doi.org/10.1038/nrd.2018.55
