NAMPT Is the Cellular Target of STF-31-Like Small-Molecule Probes

The small-molecule probes STF-31
and its analogue compound 146 were discovered while searching for
compounds that kill VHL-deficient renal cell carcinoma cell lines
selectively and have been reported to act via direct inhibition of
the glucose transporter GLUT1. We profiled the sensitivity of 679
cancer cell lines to STF-31 and found that the pattern of response
is tightly correlated with sensitivity to three different inhibitors
of nicotinamide phosphoribosyltransferase (NAMPT). We also performed
whole-exome next-generation sequencing of compound 146-resistant HCT116
clones and identified a recurrent NAMPT-H191R mutation. Ectopic expression
of NAMPT-H191R conferred resistance to both STF-31 and compound 146
in cell lines. We further demonstrated that both STF-31 and compound
146 inhibit the enzymatic activity of NAMPT in a biochemical assay
in vitro. Together, our cancer-cell profiling and genomic approaches
identify NAMPT inhibition as a critical mechanism by which STF-31-like
compounds inhibit cancer cells.