title: Chemical proteomics identifies Nampt as the target of CB30865, an orphan cytotoxic compound.
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.
authors.affiliation: Department of Discovery Biology, Myriad Pharmaceuticals, Salt Lake City, UT 84108, USA.
authors.forename: Tracey C
authors.initials: TC
authors.lastname: Fleischer
authors.forename: Brett R
authors.initials: BR
authors.lastname: Murphy
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Flick
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Terry-Lorenzo
authors.forename: Zhong-Hua
authors.initials: ZH
authors.lastname: Gao
authors.forename: Thaylon
authors.initials: T
authors.lastname: Davis
authors.forename: Rena
authors.initials: R
authors.lastname: McKinnon
authors.forename: Kirill
authors.initials: K
authors.lastname: Ostanin
authors.forename: J Adam
authors.initials: JA
authors.lastname: Willardsen
authors.forename: J Jay
authors.initials: JJ
authors.lastname: Boniface
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D055808:Drug Discovery; D045325:HCT116 Cells; D006801:Humans; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009965:Orphan Drug Production; D040901:Proteomics / Q000379:methods*; D011799:Quinazolines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C403613:CB 30865; D011799:Quinazolines; D054409:Nicotinamide Phosphoribosyltransferase