1 research outputs found
Development of New Deoxycytidine Kinase Inhibitors and Noninvasive in Vivo Evaluation Using Positron Emission Tomography
Combined
inhibition of ribonucleotide reductase and deoxycytidine
kinase (dCK) in multiple cancer cell lines depletes deoxycytidine
triphosphate pools leading to DNA replication stress, cell cycle arrest,
and apoptosis. Evidence implicating dCK in cancer cell proliferation
and survival stimulated our interest in developing small molecule
dCK inhibitors. Following a high throughput screen of a diverse chemical
library, a structure–activity relationship study was carried
out. Positron Emission Tomography (PET) using <sup>18</sup>F-L-1-(2′-deoxy-2′-<b>F</b>luoro<b>A</b>rabinofuranosyl) <b>C</b>ytosine
(<sup>18</sup>F-L-FAC), a dCK-specific substrate, was used to rapidly
rank lead compounds based on their ability to inhibit dCK activity <i>in vivo.</i> Evaluation of a subset of the most potent compounds
in cell culture (IC<sub>50</sub> = ∼1–12 nM) using the <sup>18</sup>F-L-FAC PET pharmacodynamic assay identified compounds demonstrating
superior in vivo efficacy