Investigating NFE2L1 Activators for Targeted Protein Aggregate Clearance: A Follow-Up Study

Abstract

Disruption of protein homeostasis (proteostasis), whether by acute proteotoxic stress or chronic expression of mutantproteins, can lead to the accumulation of toxic protein aggregates. Such aggregation is a hallmark of numerous diseases andis often associated with impaired protein clearance mechanisms. The transcription factor Nuclear Factor Erythroid 2-relatedFactor 1 (encoded by NFE2L1, also known as Nrf1) plays a central role in restoring proteostasis by increasing proteasomesynthesis. Therefore, pharmacological activation of NFE2L1 under non-stress conditions represents a promising therapeuticstrategy for neurodegenerative and other proteostasis-related diseases. In our previous study, we identifiedbis(phenylmethylene)cycloalkanones derivatives as NFE2L1 activators capable of inducing proteasome subunits expression,increasing heat shock protein levels, and stimulating autophagy. Building upon these findings, we have now developed anew library of structurally related compounds to identify novel more potent NFE2L1 activators. By systematically examininghow specific chemical substitutions affect NFE2L1 activation, this work advances our understanding of the structure-activityrelationships within this pathway.