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Front Pharmacol. 2017 Feb 15;8:54. doi: 10.3389/fphar.2017.00054. eCollection 2017.

Substrate-Dependence of Competitive Nucleotide Pyrophosphatase/Phosphodiesterase1 (NPP1) Inhibitors.

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PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn Bonn, Germany.
Laboratory of Medicinal Chemistry, KU Leuven, Rega Institute for Medical Research Leuven, Belgium.
Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research Dresden, Germany.


Nucleotide pyrophosphatase/phosphodiesterase type 1 (NPP1) is a membrane glycoprotein involved in the hydrolysis of extracellular nucleotides. Its major substrate is ATP which is converted to AMP and diphosphate. NPP1 was proposed as a new therapeutic target in brain cancer and immuno-oncology. Several NPP1 inhibitors have been reported to date, most of which were evaluated vs. the artificial substrate p-nitrophenyl 5'-thymidine monophosphate (p-Nph-5'-TMP). Recently, we observed large discrepancies in inhibitory potencies for a class of competitive NPP1 inhibitors when tested vs. the artificial substrate p-Nph-5'-TMP as compared to the natural substrate ATP. Therefore, the goal of the present study was to investigate whether inhibitors of human NPP1 generally display substrate-dependent inhibitory potency. Systematic evaluation of nucleotidic as well as non-nucleotidic NPP1 inhibitors revealed significant differences in determined Ki values for competitive, but not for non- and un-competitive inhibitors when tested vs. the frequently used artificial substrate p-Nph-5'-TMP as compared to ATP. Allosteric modulation of NPP1 by p-Nph-5'-TMP may explain these discrepancies. Results obtained using the AMP derivative p-nitrophenyl 5'-adenosine monophosphate (p-Nph-5'-AMP) as an alternative artificial substrate correlated much better with those employing the natural substrate ATP.


NPP1; NPP1 inhibitors; ectonucleotidase inhibitors; enzyme assay; nucleotide pyrophosphatase 1; p-nitrophenyl 5′-thymidine monophosphate

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