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Inhibition of firefly luciferase activity by a HIF prolyl hydroxylase inhibitor


Scholz, Carsten; Günter, Julia; Wenger, Roland H.; Scholz, Carsten C. (2020), Inhibition of firefly luciferase activity by a HIF prolyl hydroxylase inhibitor, Dryad, Dataset,


The three hypoxia-inducible factor (HIF) prolyl-4-hydroxylase domain (PHD) 1–3 enzymes confer oxygen sen-sitivity to the HIF pathway and are novel therapeutic targets for treatment of renal anemia. Inhibition of thePHDs may further be beneficial in other hypoxia-associated diseases, including ischemia and chronic in-flammation. Several pharmacologic PHD inhibitors (PHIs) are available, but our understanding of their selectivity and its chemical basis is limited.We here report that the PHI JNJ-42041935 (JNJ-1935) is structurally similar to the firefly luciferase substrate D-luciferin. Our results demonstrate that JNJ-1935 is a novel inhibitor of firefly luciferase enzymatic activity. In contrast, the PHIs FG-4592 (roxadustat) and FG-2216 (ICA,BIQ,IOX3,YM311) did not affect firefly luciferase. The JNJ-1935 mode of inhibition is competitive with a Ki of 1.36 μM. D-luciferin did not inhibit the PHDs, despite its structural similarity to JNJ-1935. This study provides insights into a previously unknown JNJ-1935 off-target effect as well as into the chemical requirements for firefly luciferase and PHD inhibitors and may inform the development of novel compounds targeting these enzymes.


Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Award: 310030_184813

Swiss National Centre of Competence in Research Kidney Control of Homeostasis, Award: Junior Grant