PROTACs therapeutically target the polyglutamine androgen receptor in spinal and bulbar muscular atrophy models

  • Neurotherapeutics. 2025 Oct;22(6):e00732. doi: 10.1016/j.neurot.2025.e00732.
Agamjot Sangotra  1 ,  Satya L Reddy  1 ,  Curtis J Kuo  1 ,  Weiguo Xiang  2 ,  Diane E Merry  3 ,  Christopher Grunseich  4 ,  Shaomeng Wang  2 ,  Andrew P Lieberman  5
Affiliations
  • 1. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 2. Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • 3. Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
  • 4. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • 5. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address: [email protected].
PMID: 40912964 DOI: 10.1016/j.neurot.2025.e00732
Abstract

Spinal and bulbar muscular atrophy (SBMA) is a CAG/polyglutamine (polyQ) repeat expansion disorder in which the mutant Androgen Receptor (AR) protein triggers progressive degeneration of the neuromuscular system in men. As the misfolded polyQ AR is the proximal mediator of toxicity, therapeutic efforts have focused on targeting the mutant protein, but these prior efforts have met with limited success in SBMA patients. Here, we examine the efficacy of small molecule AR proteolysis-targeting chimera (PROTAC) degraders that rapidly and potently promote AR ubiquitination and degradation by the Proteasome. We show that the AR PROTAC degrader ARD-1676 clears polyQ AR in an over-expression system, in patient iPSC-derived induced motor neurons and skeletal muscle cells, and in a gene targeted mouse model of disease. Furthermore, we demonstrate that 24-h treatment with ARD-1676 rescues transcriptional dysregulation in SBMA induced skeletal muscle cells. These data provide evidence of therapeutic efficacy and in vivo target engagement, establishing AR PROTAC degraders as potential therapeutic agents for the treatment of SBMA.

Keywords
AR PROTAC degrader; Androgen receptor; CAG/polyglutamine disorder; SBMA.
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