Target identification and SAR of the Nampt inhibitor CB30865.

Abstract

Drug discovery based on cellular phenotypes is impeded by the lack of knowledge concerning the mol. target responsible for that phenotype. To address this shortcoming, Myrexis has developed a chem. proteomics technol. to identify cellular proteins that bind to biol. active small mols. CB30865 was shown to be a compd. with potent tumoricidal activity, but with unknown mechanism of action. Using our technol., we have demonstrated that the tumoricidal activity of CB30865 is due to inhibition of nicotinamide phosphoribosyltransferase (Nampt). With its cellular target known, we sought to optimize both the biochem. and cellular activities of CB30865. It was detd. that the 3-pyridylmethyl amide was crit. for tumoricidal potency. Small, unsatd. groups attached to the analinic nitrogen were optimal, with 3,3-dimethylallyl yielding the greatest potency. Also, the distal region required a quinazolin-4-one or 1,2,3-benzotriazin-4-one group for optimal activity. [on SciFinder(R)]