Journal
BIOORGANIC CHEMISTRY
Volume 108, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2020.104614
Keywords
ARE activator; NRF2; PGK1 inhibitor; Structure activity relationship; Reactive metabolites
Funding
- Skaggs Institute for Chemical Biology at Scripps Research
- Bio & Medical Technology Development Program of the National Research Foundation (NRF) - Korean government (MSIT) [NRF-2017M3A9G7072568]
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NRF2 is an important therapeutic target for enhancing resistance to oxidative damage by activating cellular mechanisms. A series of bis-sulfones derived from an unexplored chemical template show promising potential as efficient NRF2 activators, with some analogs also exhibiting non-toxic properties.
The transcription factor NRF2 controls resistance to oxidative insult and is thus a key therapeutic target for treating a number of disease states associated with oxidative stress and aging. We previously reported CBR-470-1, a bis-sulfone which activates NRF2 by increasing the levels of methylglyoxal, a metabolite that covalently modifies NRF2 repressor KEAP1. Here, we report the design, synthesis, and structure activity relationship of a series of bis-sulfones derived from this unexplored chemical template. We identify analogs with sub-micromolar potencies, 7f and 7g, as well as establish that efficacious NRF2 activation can be achieved by non-toxic analogs 7c, 7e, and 9, a key limitation with CBR-470-1. Further efforts to identify non-covalent NRF2 activators of this kind will likely provide new insight into revealing the role of central metabolism in cellular signaling.
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