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Investigating NFE2L1 activators for targeted protein aggregate clearance: a follow-up study
Zuzana Smahelova1,2, Lucie Svobodova1,3, Jindrich Sedlacek1,2
1Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo n. 542/2 160 00 Prague 6 Czech Republic ales.machara@uochb.cas.cz.
RSC Medicinal Chemistry
|November 14, 2025
Summary
Researchers developed new compounds to activate nuclear factor erythroid 2-related factor 1 (NFE2L1), enhancing protein homeostasis. This strategy holds promise for treating diseases linked to protein aggregation and impaired clearance mechanisms.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Protein homeostasis (proteostasis) disruption leads to toxic aggregate accumulation, a hallmark of many diseases.
- Impaired protein clearance mechanisms often accompany proteostasis loss.
- Nuclear factor erythroid 2-related factor 1 (NFE2L1) transcription factor is crucial for restoring proteostasis via proteasome synthesis.
Purpose of the Study:
- To identify novel, more potent activators of NFE2L1.
- To explore structure-activity relationships of bis(phenylmethylene)cycloalkanone derivatives for NFE2L1 activation.
- To advance therapeutic strategies for proteostasis-related diseases through NFE2L1 pharmacological activation.
Main Methods:
- Systematic synthesis of a new library of bis(phenylmethylene)cycloalkanone derivatives.
- Evaluation of NFE2L1 activation potency through chemical structure modifications.
- Analysis of structure-activity relationships to guide compound design.
Main Results:
- Discovery of novel compounds with enhanced NFE2L1 activating properties.
- Identification of key chemical substitutions influencing NFE2L1 activation.
- Demonstration of improved proteasome synthesis and cellular proteostasis.
Conclusions:
- Pharmacological activation of NFE2L1 is a viable therapeutic strategy for proteostasis disorders.
- The developed compounds represent promising leads for treating neurodegenerative and other related diseases.
- Understanding structure-activity relationships is key to optimizing NFE2L1 activators.
