Identification of a Selective SCoR2 Inhibitor That Protects Against Acute Kidney Injury

Acute kidney injury (AKI) is associated with high morbidity
and
mortality, and no drugs are available clinically. Metabolic reprogramming
resulting from the deletion of S-nitroso-coenzyme A reductase 2 (SCoR2;
AKR1A1) protects mice against AKI, identifying SCoR2 as a potential
drug target. Of the few known inhibitors of SCoR2, none are selective
versus the related oxidoreductase AKR1B1, limiting therapeutic utility.
To identify SCoR2 (AKR1A1) inhibitors with selectivity versus AKR1B1,
analogs of the nonselective (dual 1A1/1B1) inhibitor imirestat were
designed, synthesized, and evaluated. Among 57 compounds, JSD26 has
10-fold selectivity for SCoR2 versus AKR1B1 and inhibits SCoR2 potently
through an uncompetitive mechanism. When dosed orally to mice, JSD26
inhibited SNO-CoA metabolic activity in multiple organs. Notably,
intraperitoneal injection of JSD26 in mice protected against AKI through
S-nitrosylation of pyruvate kinase M2 (PKM2), whereas imirestat was
not protective. Thus, selective inhibition of SCoR2 has therapeutic
potential to treat acute kidney injury.