Metabolic Modifier Screen Reveals Secondary Targets of Protein Kinase Inhibitors within Nucleotide Metabolism
25 Pages Posted: 19 May 2019 Sneak Peek Status: Under ReviewMore...
A cell-based metabolic modifier screening platform for the discovery of modulators of convergent pyrimidine nucleotide biosynthetic pathways was designed and implemented. In screening a library of protein kinase inhibitors, multiple compounds were shown to possess previously uncharacterized nucleotide metabolism-modifying activity. The JNK inhibitor JNK-IN-8 was found to be a potent inhibitor of nucleoside transport, a property which was confirmed using nucleoside-analog Positron Emission Tomography (PET) imaging in mice. The PDK1 inhibitor OSU-03012 (also known as AR-12) and the RAF inhibitor TAK-632 were shown to inhibit the therapeutically relevant enzyme dihydroorotate dehydrogenase (DHODH) and their affinities were unambiguously confirmed through in vitro assays and co-crystallization with human DHODH.
Keywords: Pyrimidine metabolism, cancer metabolism, phenotypic screening, target identification
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