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ACS Chem Biol DOI:10.1021/cb500347p

NAMPT is the cellular target of STF-31-like small-molecule probes.

Publication TypeJournal Article
Year of Publication2014
AuthorsAdams, DJ, Ito, D, Rees, MG, Seashore-Ludlow, B, Puyang, X, Ramos, AH, Cheah, JH, Clemons, PA, Warmuth, M, Zhu, P, Shamji, AF, Schreiber, SL
JournalACS Chem Biol
Date Published2014 Oct 17
KeywordsBiomarkers, Tumor, Blotting, Western, Cell Survival, Cytokines, Drug Resistance, Neoplasm, Enzyme Inhibitors, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Humans, Molecular Structure, Mutation, Neoplasms, Nicotinamide Phosphoribosyltransferase, Oligonucleotide Array Sequence Analysis, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Small Molecule Libraries, Tumor Cells, Cultured

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.


Alternate JournalACS Chem. Biol.
PubMed ID25058389
PubMed Central IDPMC4201331
Grant ListU01 CA176152 / CA / NCI NIH HHS / United States
U01CA176152 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States