Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy

  • Nat Med. 2018 May;24(4):427-437. doi: 10.1038/nm.4500.
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 L Sopher  5 ,  Jennifer Dearman  1 ,  James Messing  1  2 ,  Nam Chul Kim  1 ,  Jennifer Moore  1 ,  Brian D Freibaum  1 ,  Anderson P Kanagaraj  1 ,  Baochang Fan  1 ,  Heather Tillman  6 ,  Ping-Chung Chen  7 ,  Yingzhe Wang  4 ,  Burgess B Freeman III  4 ,  Yimei Li  8 ,  Hong Joo Kim  1 ,  Albert R La Spada  3  9 ,  J Paul Taylor  1  2
Affiliations
  • 1. Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 2. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • 3. Department of Pediatrics, University of California at San Diego, La Jolla, California, USA.
  • 4. Preclinical Pharmacokinetic Shared Resource, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 5. Department of Neurology, University of Washington, Seattle, Washington, USA.
  • 6. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 7. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 8. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 9. Departments of Neurology, Neurobiology and Cell Biology, and the Duke Center for Neurodegeneration & Neurotherapeutics, Durham, North Carolina, USA.
PMID: 29505030 DOI: 10.1038/nm.4500
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.

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