title: NAMPT is the cellular target of STF-31-like small-molecule probes.
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.
authors: Center for the Science of Therapeutics and ∥Howard Hughes Medical Institute, Broad Institute , 7 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors: Drew J
authors: DJ
authors: Adams
authors: Daisuke
authors: D
authors: Ito
authors: Matthew G
authors: MG
authors: Rees
authors: Brinton
authors: B
authors: Seashore-Ludlow
authors: Xiaoling
authors: X
authors: Puyang
authors: Alex H
authors: AH
authors: Ramos
authors: Jaime H
authors: JH
authors: Cheah
authors: Paul A
authors: PA
authors: Clemons
authors: Markus
authors: M
authors: Warmuth
authors: Ping
authors: P
authors: Zhu
authors: Alykhan F
authors: AF
authors: Shamji
authors: Stuart L
authors: SL
authors: Schreiber
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects*; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D016207:Cytokines; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D054852:Small Molecule Libraries; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human