A bioactive ligand-conjugated iridium(III) metal-based complex as a Keap1-Nrf2 protein-protein interaction inhibitor against acetaminophen-induced acute liver injury

Hepatotoxicity caused by an overdose of acetaminophen (APAP) is the leading reason for acute drug-related liver failure. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a protein that helps to regulate redox homeostasis and coordinate stress responses via binding to the Kelch-like ECH-associated protein 1 (Keap1). Targeting the Keap1-Nrf2 interaction has recently emerged as a potential strategy to alleviate liver injury caused by APAP. Here, we designed and synthesized a number of iridium (III) and rhodium (III) complexes bearing ligands with reported activity against oxidative stress, which is associated with Nrf2 transcriptional activation. The iridium (III) complex 1 bearing a bioactive ligand 2,9-dimethyl-1,10-phenanthroline and 4-chloro-2-phenylquinoline, a derivative of the bioactive ligand 2-phenylquinoline, was identified as a direct small-molecule inhibitor of the Keap1-Nrf2 protein-protein interaction. 1 could stabilize Keap1 protein, upregulate HO-1 and NQO1, and promote Nrf2 nuclear translocation in normal liver cells. Moreover, 1 reversed APAP-induced liver damage by disrupting Keap1-Nrf2 interaction and without inducing organ damage and immunotoxicity in mice. Our study demonstrates the identification of a selective and efficacious antagonist of Keap1-Nrf2 interaction possessed good cellular permeability in cellulo and ideal pharmacokinetic parameters in vivo, and, more importantly, validates the feasibility of conjugating metal complexes with bioactive ligands to generate metal-based drug leads as non-toxic Keap1-Nrf2 interaction inhibitors for treating APAP-induced acute liver injury.