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Pharmacological Activation of Metal Responsive Transcription Factor 1 by Liganding of Nucleophosmin

ABSTRACT: Metal responsive transcription factor-1 (MTF-1) enacts a pro-protective, homeostatic transcriptional program in response to heavy metal stress. Activation of MTF-1 in model organisms protects against heavy metal toxicity, forestalls neurodegeneration, and extends life, suggesting that pharmacological agents which augment MTF-1 driven transcription may have the potential to ameliorate pathology associated with heavy metals. Here, we report the discovery of sARM518, a small molecule which robustly activates MTF-1 transcriptional activity in human cells and protects against heavy metal and oxidative stress. Chemical proteomics revealed the cellular target of sARM518 to be nucleophosmin (NPM1), a protein that directly associates with zinc-bound MTF-1 in response to sARM518 treatment, promoting a nuclear, transcriptionally active form of MTF-1. This work affords the first pharmacological activator of MTF-1 and establishes NPM1 as a central, druggable regulator of a cellular stress response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290711 | GEO | 2026/09/30

REPOSITORIES: GEO

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