Related Experiment Video
Updated: Apr 26, 2026
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
NAMPT is the cellular target of STF-31-like small-molecule probes
Drew J Adams1, Daisuke Ito, Matthew G Rees
1Center for the Science of Therapeutics and ∥Howard Hughes Medical Institute, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
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.
Insights
Small-molecule probes STF-31 and compound 146 selectively kill VHL-deficient renal cell carcinoma cells by inhibiting nicotinamide phosphoribosyltransferase (NAMPT), not glucose transporter 1 (GLUT1). This discovery offers new therapeutic targets for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- STF-31 and compound 146 were identified as potential VHL-deficient renal cell carcinoma treatments, initially thought to target glucose transporter 1 (GLUT1).
- Cancer cell line profiling revealed a strong correlation between sensitivity to these compounds and sensitivity to nicotinamide phosphoribosyltransferase (NAMPT) inhibitors.
Discussion:
- Genomic analysis of resistant cell lines identified a specific NAMPT mutation (NAMPT-H191R) conferring resistance to STF-31 and compound 146.
- Biochemical assays confirmed that STF-31 and compound 146 directly inhibit NAMPT enzymatic activity in vitro.
Key Insights:
- The primary mechanism of action for STF-31 and compound 146 is the inhibition of NAMPT, a key enzyme in cellular metabolism.
- This finding redefines the therapeutic target of these compounds from GLUT1 to NAMPT.
Outlook:
- Targeting NAMPT presents a novel therapeutic strategy for VHL-deficient renal cell carcinoma and potentially other cancers.
- Further research into NAMPT inhibitors could lead to the development of more effective cancer therapies.
