title: Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) as a therapeutic strategy in cancer.
abstract: NAD is a metabolite that is an important cofactor and second messenger for a number of cellular processes such as genomic stability and metabolism that are essential for survival. NAD is generated de novo from tryptophan or recycled from NAM through the NAMPT-dependent salvage pathway. Alternatively, cells can convert NA to NAD through the NAPRT1-dependent salvage pathway. Tumor cells rapidly turn over NAD but do not efficiently utilize the de novo synthesis pathway. Hence, they are more reliant on the NAMPT salvage pathway for NAD regeneration making this enzyme an attractive therapeutic target for cancer. NAMPT is over-expressed in a number of cancer types such as colorectal, ovarian, breast, gastric, prostate, gliomas as well as B-cell lymphomas. A number of novel, potent and selective NAMPT small molecule inhibitors have been synthesized to date that have displayed robust anti-tumor activity in tumor models in vitro and in vivo. These inhibitors efficiently suppress NAD production in a time dependent manner and sustained reduction of NAD levels leads to loss of ATP and ultimately cell death. This review will summarize the chemical properties of these unique NAMPT inhibitors as well as their mechanism of action, pharmacodynamic activity and efficacy in tumor models in vitro and in vivo. An overview of biomarkers that predict response to treatment and mechanisms of resistance to NAMPT inhibitors will also be provided. Additionally, NAMPT inhibitors that have advanced into clinical trials will be reviewed along with experimental strategies tested to potentially increase the therapeutic index of these inhibitors.
authors.affiliation: Department of Translational Oncology, Genentech Research and Early Development, South San Francisco, CA 94080, USA. Electronic address: dsampath@gene.com.
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.affiliation: Department of Safety Assessment, Genentech Research and Early Development, South San Francisco, CA 94080, USA.
authors.forename: Tanja S
authors.initials: TS
authors.lastname: Zabka
authors.affiliation: Department of Safety Assessment, Genentech Research and Early Development, South San Francisco, CA 94080, USA.
authors.forename: Dinah L
authors.initials: DL
authors.lastname: Misner
authors.affiliation: Department of Translational Oncology, Genentech Research and Early Development, South San Francisco, CA 94080, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Brien
authors.affiliation: Department of Discovery Chemistry, Genentech Research and Early Development, South San Francisco, CA 94080, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D002986:Clinical Trials as Topic; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D009525:Niacin / Q000494:pharmacology / Q000627:therapeutic use; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009525:Niacin; D054409:Nicotinamide Phosphoribosyltransferase
keywords: NAD; NAMPT; NAPRT1; Targeted agents; Tumor metabolism