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

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

Drew J Adams, Daisuke Ito, Matthew G Rees, Brinton Seashore-Ludlow, Xiaoling Puyang, Alex H Ramos, Jaime H Cheah, Paul A Clemons, Markus Warmuth, Ping Zhu, Alykhan F Shamji, Stuart L Schreiber

ACS Chem Biol. 2014 Oct 17;9(10):2247-54.

PMID: 25058389

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP724741757	STF-31		724741-75-7	Price

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