Bivalent KEAP1 inhibitor for acute inflammatory diseases

A bivalent inhibitor of the E3 ubiquitin ligase KEAP1 could help treat acute inflammation by blocking both of its binding sites for the transcription factor NRF2, releasing bound NRF2 faster than monomeric KEAP1 inhibitors, and thus better enabling NRF2-mediated cell survival and redox homeostasis.

In cell-based reporter assays, six bivalent KEAP1 inhibitors, created by conjugating two molecules of a previously identified monomeric inhibitor via linkers of different lengths, were screened for the ability to induce NRF2 nuclear translocation and transcriptional activity. A compound with an EC50 of 98.72nM that induced NRF2-dependent transcriptional responses more potently and quickly than known NRF2-inducing compounds, including the monomeric KEAP1 inhibitor, was selected for follow-up studies. ...