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Identification of Natural Product Sulfuretin Derivatives as Inhibitors for the Endoplasmic Reticulum Redox Protein ERO1α

[Image: see text] The flavin adenine dinucleotide containing endoplasmic reticulum oxidoreductase-1 α (ERO1α) catalyzes the de novo disulfide bond formation of secretory and transmembrane proteins and contributes toward proper protein folding. Recently, increased ERO1α expression has been shown to c...

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Detalles Bibliográficos
Autores principales: Johnson, Brennan D., Kaulagari, Sridhar Reddy, Chen, Wei-Chih, Hayes, Karen, Geldenhuys, Werner J., Hazlehurst, Lori A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9312093/
https://www.ncbi.nlm.nih.gov/pubmed/35892127
http://dx.doi.org/10.1021/acsbiomedchemau.1c00062
Descripción
Sumario:[Image: see text] The flavin adenine dinucleotide containing endoplasmic reticulum oxidoreductase-1 α (ERO1α) catalyzes the de novo disulfide bond formation of secretory and transmembrane proteins and contributes toward proper protein folding. Recently, increased ERO1α expression has been shown to contribute to increased tumor growth and metastasis in multiple cancer types. In this report, we sought to define novel chemical space for targeting ERO1α function. Using the previously reported ERO1α inhibitor compound, EN-460, as a benchmark pharmacological tool, we were able to identify a sulfuretin derivative, T151742, which was approximately 2-fold more potent using a recombinant enzyme assay system (IC(50) = 8.27 ± 2.33 μM) compared to EN-460 (IC(50)= 16.46 ± 3.47 μM). Additionally, T151742 (IC(50) = 16.04 μM) was slightly more sensitive than EN-460 (IC(50)= 19.35μM), using an MTT assay as an end point. Utilizing a cellular thermal shift assay (CETSA), we determined that the sulfuretin derivative T151742 demonstrated isozyme specificity for ERO1α as compared to that for ERO1β and showed no detectable binding to the FAD-containing enzyme LSD-1. T151742 retained activity in PC-9 cells in a clonogenicity assay, while EN-460 was devoid of activity. Furthermore, the activity of T151742 inhibition of clonogenicity was dependent on ERO1α expression as CRISPR-edited PC-9 cells were resistant to treatment with T151742. In summary, we identified a new scaffold that shows specificity for ERO1α compared to that for the closely related paralog ERO1β or the FAD-containing enzyme LSD-1 that can be used as a tool compound for the inhibition of ERO1α to allow for pharmacological validation of the role of ERO1α in cancer.