STF 31

STF-31 is an inhibitor of glucose transporter 1 (GLUT1, IC50 = 1 μM). IC50 value: 1 μM Target: GLUT1 in vitro: STF 31 is a glucose uptake inhibitor in RCC (renal cell carcinoma) 4 cells. By limiting glucose uptake in cancer cells, the immense energy requirements for the cancer cell is not met and the cell does not have the resources to rapidly proliferate.STF-31, which selectively kills RCCs by specifically targeting glucose uptake through GLUT1 and exploiting the unique dependence of these cells on GLUT1 for survival. STF-31 decreases glycolysis by decreasing glucose transport and not by inhibiting a particular glycolytic step or enzyme.[1] in vivo: STF-31 selectively targets the von Hippel-Lindau (VHL)-deficient kidney cancer cells. STF-31 inhibits VHL-deficient cancer cells by inhibiting Glut1. Daily intraperitoneal injection of a soluble analogue of STF-31 effectively reduces the growth of tumors of VHL-deficient cancer cells grafted on nude mice. On the other hand, STF-31 appears to be an inhibitor with a narrow cell target spectrum.[2]

References:
[1]. Chan DA, et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci Transl Med. 2011 Aug 3;3(94):94ra70. [2]. Liu Y, et al. A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, andinhibits cancer cell growth in vitro and in vivo. Mol Cancer Ther. 2012 Aug;11(8):1672-1682.

NAMPT is the cellular target of STF-31-like small-molecule probes.[Pubmed:25058389]

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

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.

Inhibition of an NAD(+) salvage pathway provides efficient and selective toxicity to human pluripotent stem cells.[Pubmed:25834119]

Stem Cells Transl Med. 2015 May;4(5):483-93.

The tumorigenic potential of human pluripotent stem cells (hPSCs) is a major limitation to the widespread use of hPSC derivatives in the clinic. Here, we demonstrate that the small molecule STF-31 is effective at eliminating undifferentiated hPSCs across a broad range of cell culture conditions with important advantages over previously described methods that target metabolic processes. Although STF-31 was originally described as an inhibitor of glucose transporter 1, these data support the reclassification of STF-31 as a specific NAD(+) salvage pathway inhibitor through the inhibition of nicotinamide phosphoribosyltransferase (NAMPT). These findings demonstrate the importance of an NAD(+) salvage pathway in hPSC biology and describe how inhibition of NAMPT can effectively eliminate hPSCs from culture. These results will advance and accelerate the development of safe, clinically relevant hPSC-derived cell-based therapies.

Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality.[Pubmed:21813754]

Sci Transl Med. 2011 Aug 3;3(94):94ra70.

Identifying new targeted therapies that kill tumor cells while sparing normal tissue is a major challenge of cancer research. Using a high-throughput chemical synthetic lethal screen, we sought to identify compounds that exploit the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in about 80% of renal cell carcinomas (RCCs). RCCs, like many other cancers, are dependent on aerobic glycolysis for ATP production, a phenomenon known as the Warburg effect. The dependence of RCCs on glycolysis is in part a result of induction of glucose transporter 1 (GLUT1). Here, we report the identification of a class of compounds, the 3-series, exemplified by STF-31, which selectively kills RCCs by specifically targeting glucose uptake through GLUT1 and exploiting the unique dependence of these cells on GLUT1 for survival. Treatment with these agents inhibits the growth of RCCs by binding GLUT1 directly and impeding glucose uptake in vivo without toxicity to normal tissue. Activity of STF-31 in these experimental renal tumors can be monitored by [(18)F]fluorodeoxyglucose uptake by micro-positron emission tomography imaging, and therefore, these agents may be readily tested clinically in human tumors. Our results show that the Warburg effect confers distinct characteristics on tumor cells that can be selectively targeted for therapy.