2. Academic Validation
  3. Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy

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

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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