Nicotinamide adenine dinucleotide (NAD) is an important biomolecule implicated in a large number of cellular processes ranging from cell metabolism and survival to calcium homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first and rate-determining step of recycling nicotinamide (NAM) back to NAD. Blockade of the NAM-NAD recycling pathway via NAMPT inhibition might be an appropriate therapeutic strategy for oncology indications [3]. GNE-617 inhibits human NAMPT in a biochemical assay with an IC50 of 5 nM and reduces NAD levels across a panel of six diverse cancer cell lines with a t1/2 of NAD reduction ranging from 6.5 to 12.5 h. NAD depletion caused by GNE-617 results in cell death, with an observed increase in a sub2N population. Cell growth was attenuated within 32–40 h in A549, Calu6, HCT116, and PC-3 cells following treatment with 200 nM GNE-617 for 138 h. To measure cell motility, the change in location for 100 individual cells was tracked hourly for 102 h following exposure to 200 nM GNE-617. Control A549 and Calu6 cells displayed an average motility of 15.1 ± 1.7 and 10.2 ± 1.1 μM per hour, respectively, whereas cells exposed to GNE-617 showed a decrease in motility starting as early as 21 h, corresponding to the case when NAD levels have decreased by 95% [4].
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