2 research outputs found
Structure-Guided Development of Deoxycytidine Kinase Inhibitors with Nanomolar Affinity and Improved Metabolic Stability
Recently,
we have shown that small molecule dCK inhibitors in combination
with pharmacological perturbations of de novo dNTP biosynthetic pathways
could eliminate acute lymphoblastic leukemia cells in animal models.
However, our previous lead compound had a short half-life in vivo. Therefore, we set out to develop dCK inhibitors with favorable pharmacokinetic
properties. We delineated the sites of the inhibitor for modification,
guided by crystal structures of dCK in complex with the lead compound
and with derivatives. Crystal structure of the complex between dCK
and the racemic mixture of our new lead compound indicated that the <i>R</i>-isomer is responsible for kinase inhibition. This was
corroborated by kinetic analysis of the purified enantiomers, which
showed that the <i>R</i>-isomer has >60-fold higher affinity
than the <i>S</i>-isomer for dCK. This new lead compound
has significantly improved metabolic stability, making it a prime
candidate for dCK-inhibitor based therapies against hematological
malignancies and, potentially, other cancers
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