Chemical Proteomics Identifies Nampt as the Target of CB30865, An Orphan Cytotoxic Compound

Tracey C. Fleischer, Brett R. Murphy, Jeffrey S. Flick, Ryan T. Terry-Lorenzo, Zhong Hua Gao, Thaylon Davis, Rena McKinnon, Kirill Ostanin, J. Adam Willardsen, J. Jay Boniface

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Drug discovery based on cellular phenotypes is impeded by the challenge of identifying the molecular target. To alleviate this problem, we developed a chemical proteomic process to identify cellular proteins that bind to small molecules. CB30865 is a potent (subnanomolar) and selective cytotoxic compound of previously unknown mechanism of action. By combining chemical proteomics with biochemical and cellular pharmacology we have determined that CB30865 cytotoxicity is due to subnanomolar inhibition of nicotinamide phosphoribosyltransferase (Nampt), an enzyme present in the NAD biosynthetic pathway. Cancer cells develop dependence on Nampt due to increased energy requirements and the elevated activity of NAD consuming enzymes such as sirtuins and mono and poly(ADP-ribose) polymerases (PARPs). These findings suggest new chemical starting points for Nampt inhibitors and further implicate this enzyme as a target in cancer.

Original languageEnglish (US)
Pages (from-to)659-664
Number of pages6
JournalChemistry and Biology
Volume17
Issue number6
DOIs
StatePublished - Jun 25 2010

Fingerprint

Nicotinamide Phosphoribosyltransferase
Proteomics
NAD
Enzymes
Chemical Phenomena
Sirtuins
Poly(ADP-ribose) Polymerases
Biosynthetic Pathways
Drug Discovery
Cytotoxicity
Neoplasms
Cells
Pharmacology
Phenotype
Molecules
CB 30865
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Fleischer, T. C., Murphy, B. R., Flick, J. S., Terry-Lorenzo, R. T., Gao, Z. H., Davis, T., ... Boniface, J. J. (2010). Chemical Proteomics Identifies Nampt as the Target of CB30865, An Orphan Cytotoxic Compound. Chemistry and Biology, 17(6), 659-664. https://doi.org/10.1016/j.chembiol.2010.05.008
Fleischer, Tracey C. ; Murphy, Brett R. ; Flick, Jeffrey S. ; Terry-Lorenzo, Ryan T. ; Gao, Zhong Hua ; Davis, Thaylon ; McKinnon, Rena ; Ostanin, Kirill ; Willardsen, J. Adam ; Boniface, J. Jay. / Chemical Proteomics Identifies Nampt as the Target of CB30865, An Orphan Cytotoxic Compound. In: Chemistry and Biology. 2010 ; Vol. 17, No. 6. pp. 659-664.
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Fleischer, TC, Murphy, BR, Flick, JS, Terry-Lorenzo, RT, Gao, ZH, Davis, T, McKinnon, R, Ostanin, K, Willardsen, JA & Boniface, JJ 2010, 'Chemical Proteomics Identifies Nampt as the Target of CB30865, An Orphan Cytotoxic Compound', Chemistry and Biology, vol. 17, no. 6, pp. 659-664. https://doi.org/10.1016/j.chembiol.2010.05.008

Chemical Proteomics Identifies Nampt as the Target of CB30865, An Orphan Cytotoxic Compound. / Fleischer, Tracey C.; Murphy, Brett R.; Flick, Jeffrey S.; Terry-Lorenzo, Ryan T.; Gao, Zhong Hua; Davis, Thaylon; McKinnon, Rena; Ostanin, Kirill; Willardsen, J. Adam; Boniface, J. Jay.

In: Chemistry and Biology, Vol. 17, No. 6, 25.06.2010, p. 659-664.

Research output: Contribution to journalArticle

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