Chemical proteomics identifies Nampt as the target of CB30865, an orphan cytotoxic compound.
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.
Fleischer
Tracey C
TC
Department of Discovery Biology, Myriad Pharmaceuticals, Salt Lake City, UT 84108, USA.
Murphy
Brett R
BR
Flick
Jeffrey S
JS
Terry-Lorenzo
Ryan T
RT
Gao
Zhong-Hua
ZH
Davis
Thaylon
T
McKinnon
Rena
R
Ostanin
Kirill
K
Willardsen
J Adam
JA
Boniface
J Jay
JJ
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*
D000970:Antineoplastic Agents; C403613:CB 30865; D011799:Quinazolines; D054409:Nicotinamide Phosphoribosyltransferase