Nicotinamide adenine dinucleotide metabolism as an attractive target for drug discovery.
Nicotinamide adenine dinucleotide (NAD(+)) has crucial roles in many cellular processes, both as a coenzyme for redox reactions and as a substrate to donate ADP-ribose units. Enzymes involved in NAD(+) metabolism are attractive targets for drug discovery against a variety of human diseases, including cancer, multiple sclerosis, neurodegeneration and Huntington's disease. A small-molecule inhibitor of nicotinamide phosphoribosyltransferase, an enzyme in the salvage pathway of NAD(+) biosynthesis, is presently in clinical trials against cancer. An analog of a kynurenine pathway intermediate is efficacious against multiple sclerosis in an animal model. Indoleamine 2,3-dioxygenase plays an important role in immune evasion by cancer cells and other disease processes. Inhibitors against kynurenine 3-hydroxylase can reduce the production of neurotoxic metabolites while increasing the production of neuroprotective compounds. This review summarizes the existing knowledge on NAD(+) metabolic enzymes, with emphasis on their relevance for drug discovery.
Khan
Javed A
JA
Columbia University, Department of Biological Sciences, New York, NY 10027, USA.
Forouhar
Farhad
F
Tao
Xiao
X
Tong
Liang
L
D000178:Acrylamides / Q000494:pharmacology / Q000627:therapeutic use; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000375:Aging / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000378:metabolism; D017322:Clinical Trials, Phase II as Topic; D036563:Cyclic ADP-Ribose / Q000502:physiology; D004249:DNA Damage; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007737:Kynurenine / Q000378:metabolism; D051379:Mice; D009243:NAD / Q000378:metabolism* / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism
D000178:Acrylamides; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D018696:Neuroprotective Agents; D010880:Piperidines; D009243:NAD; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D011064:Poly Adenosine Diphosphate Ribose; D007737:Kynurenine; D014364:Tryptophan; D037761:Sirtuins