Targeting glutamine metabolism

New strategy for SBMA therapySpinal 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.