Development of a brain-penetrant G9a methylase inhibitor to target Alzheimer's disease-associated proteopathology

  • Nat Commun. 2025 May 7;16(1):4222. doi: 10.1038/s41467-025-59128-z.
Ling Xie  #  1 ,  Ryan N Sheehy  #  2 ,  Adil Muneer  #  1 ,  Yan Xiong  #  3 ,  John A Wrobel  1 ,  Feng Zhang  4 ,  Kwang-Su Park  3 ,  Julia Velez  3 ,  Jing Liu  3 ,  Yan-Jia Luo  2 ,  Brent Asrican  2 ,  Ping Dong  2 ,  Ya-Dong Li  2 ,  Corina Damian  2 ,  Luis Quintanilla  2 ,  Yongyi Li  2 ,  Chongchong Xu  5 ,  Mohanish Deshmukh  6 ,  Leon G Coleman Jr  7 ,  Guo-Li Ming  4 ,  Hongjun Song  4 ,  Zhexing Wen  5 ,  Jian Jin  8 ,  Juan Song  9 ,  Xian Chen  10  11
Affiliations
  • 1. Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 2. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 3. Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 4. Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA, USA.
  • 5. Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurology, Emory University School of Medicine, Atlanta, GA, USA.
  • 6. Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 7. Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • 8. Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
  • 9. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].
  • 10. Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].
  • 11. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].
  • # Contributed equally.
PMID: 40328756 DOI: 10.1038/s41467-025-59128-z
Abstract

Current Aβ-targeting therapeutics for Alzheimer's disease (AD) only slow cognitive decline due to poor understanding of AD pathogenesis. Here we describe a mechanism of AD pathogenesis in which the Histone Methyltransferase G9a noncanonically regulates translation of hippocampal proteins associated with AD pathology. Correspondingly, we developed a brain-penetrant inhibitor of G9a, MS1262, which restored both age-related learning & memory and noncognitive functions in multiple AD mouse models. Further, comparison of AD pathology-correlated mouse proteomes with those of AD patients found G9a regulates pathological pathways that promote Aβ and neurofibrillary tangles. This mouse-to-human overlap of G9a regulated AD-associated pathologic proteins supports at the molecular level the efficacy of targeting G9a translational mechanism for treating AD patients. Additionally, MS1262 treatment reversed the AD-characteristic expression or phosphorylation of multiple clinically validated biomarkers of AD that have the potential to be used for early-stage AD diagnosis and companion diagnosis of individualized drug effects.

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