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

Ling Xie, Ryan N. Sheehy, Adil Muneer, Yan Xiong, John A. Wrobel, Feng Zhang, Kwang-Su Park, Julia Velez, Jing Liu, Yan-Jia Luo, Brent Asrican, Ping Dong, Ya-Dong Li, Corina Damian, Luis Quintanilla, Yongyi Li, Chongchong Xu, Mohanish Deshmukh, Leon G. Coleman, Guo-Li Ming, Hongjun Song, Zhexing Wen, Jian Jin (), Juan Song () and Xian Chen ()
Additional contact information
Ling Xie: University of North Carolina at Chapel Hill
Ryan N. Sheehy: University of North Carolina at Chapel Hill
Adil Muneer: University of North Carolina at Chapel Hill
Yan Xiong: Icahn School of Medicine at Mount Sinai
John A. Wrobel: University of North Carolina at Chapel Hill
Feng Zhang: University of Pennsylvania
Kwang-Su Park: Icahn School of Medicine at Mount Sinai
Julia Velez: Icahn School of Medicine at Mount Sinai
Jing Liu: Icahn School of Medicine at Mount Sinai
Yan-Jia Luo: University of North Carolina at Chapel Hill
Brent Asrican: University of North Carolina at Chapel Hill
Ping Dong: University of North Carolina at Chapel Hill
Ya-Dong Li: University of North Carolina at Chapel Hill
Corina Damian: University of North Carolina at Chapel Hill
Luis Quintanilla: University of North Carolina at Chapel Hill
Yongyi Li: University of North Carolina at Chapel Hill
Chongchong Xu: Emory University School of Medicine
Mohanish Deshmukh: University of North Carolina at Chapel Hill
Leon G. Coleman: University of North Carolina at Chapel Hill School of Medicine
Guo-Li Ming: University of Pennsylvania
Hongjun Song: University of Pennsylvania
Zhexing Wen: Emory University School of Medicine
Jian Jin: Icahn School of Medicine at Mount Sinai
Juan Song: University of North Carolina at Chapel Hill
Xian Chen: University of North Carolina at Chapel Hill

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59128-z

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