Badders, N.M., Korff, A., Miranda, H.C., Vuppala, P.K., Smith, R.B., Winborn, B.J., Quemin, E.R., Sopher, B.L., Dearman, J., Messing, J., Kim, N.C., Moore, J., Freibaum, B.D., Kanagaraj, A.P., Fan, B., Tillman, H., Chen, P.C., Wang, Y., Iii, B.B.F., Li, Y., Kim, H.J., La Spada, A.R., Taylor, J.P. (2018). Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy.  Nat. Med. 24(4): 427--437.

FBrf0238627

Research paper

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.

PMC5975249 (PMC) (EuropePMC)