2. Academic Validation
  3. Identification of a Selective SCoR2 Inhibitor That Protects Against Acute Kidney Injury

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

  • J Med Chem. 2023 Apr 27;66(8):5657-5668. doi: 10.1021/acs.jmedchem.2c02089.
Hua-Lin Zhou 1 2 3,  Alfred Hausladen 1 2 3,  Puneet Anand 1 2 3,  Malligarjunan Rajavel 4,  Colin T Stomberski 1 2 3,  Rongli Zhang 1 2 3,  Richard T Premont 1 2 3,  William J Greenlee 3,  Focco van den Akker 4,  Jonathan S Stamler 1 2 3
Affiliations

Affiliations

  • 1 Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States.
  • 2 Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States.
  • 3 Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio 44106, United States.
  • 4 Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, United States.
PMID: 37027003 DOI: 10.1021/acs.jmedchem.2c02089
Abstract

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.

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