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 journalArticlepeer-review

44 Scopus citations

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

All Science Journal Classification (ASJC) codes

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

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