Prolyl Hydroxylase Domain Protein Inhibitor Not Harboring a 2‑Oxoglutarate Scaffold Protects against Hypoxic Stress

• Published in: ACS pharmacology & translational science Vol. 5; no. 5; pp. 362 - 372
• Main Authors: Sonoda, Kento, Bogahawaththa, Sudarma, Katayama, Akito, Ujike, Saki, Kuroki, Sae, Kitagawa, Naho, Hirotsuru, Kohichi, Suzuki, Norio, Miyata, Toshio, Kawaguchi, Shin-ichi, Tsujita, Tadayuki
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13.05.2022
• Subjects: PHD inhibitor; hypoxic stress; pyrazolidine; hypoxia inducible factor; erythropoietin
• ISSN: 2575-9108; 2575-9108
• DOI: 10.1021/acsptsci.2c00002

Hypoxia-inducible factor-α (HIF-α) activation has shown promising results in the treatment of ischemia, such as stroke, myocardial infarction, and chronic kidney disease. A number of HIF-α activators have been developed to improve the symptoms of these diseases. Many feature 2-oxoglutarate (2-OG) scaffolds that interact with the active centers of prolyl hydroxylase domain-containing proteins (PHDs), displacing the coenzyme 2-OG. This stabilizes HIF-α. Therefore, the specificity of the 2-OG analogs is not high. Here, we identified 5-(1-acetyl-5-phenylpyrazolidin-3-ylidene)-1,3-dimethylbarbituric acid (PyrzA) among over 10 000 compounds as a novel HIF activator that does not contain a 2-OG scaffold. In cultured cells, PyrzA enhanced HIF-α stability and upregulated the expression of HIF target genes. Interestingly, PyrzA decreased HIF-1α prolyl hydroxylation, suggesting that PyrzA may activate HIF to prevent the degradation of HIF-α. These results indicate that PyrzA stabilizes HIF via a novel mechanism and could be a potential HIF activator candidate.