Small Molecule Regulators Targeting NAD+ Biosynthetic Enzymes

Alyson       Curry; Dawanna       White; Yana       Cen
Abstract

Nicotinamide adenine dinucleotide (NAD+) is a key player in many metabolic pathways as an activated carrier of electrons. In addition to being the cofactor for redox reactions, NAD+ also serves as the substrate for various enzymatic transformations such as adenylation and ADP-ribosylation. Maintaining cellular NAD+ homeostasis has been suggested as an effective anti-aging strategy. Given the importance of NAD+ in regulating a broad spectrum of cellular events, small molecules targeting NAD+ metabolism have been pursued as therapeutic interventions for the treatment of mitochondrial disorders and agerelated diseases. In this article, small molecule regulators of NAD+ biosynthetic enzymes will be reviewed. The focus will be given to the discovery and development of these molecules, the mechanism of action as well as their therapeutic potentials.
Keywords: Nicotinamide adenine dinucleotide (NAD +), metabolic pathways, electrons, redox reactions, enzymatic transformations, therapeutic potentials.
[1] 
Michan, S.; Sinclair, D. Sirtuins in mammals: insights into their biological function. Biochem. J.,  2007, 404(1), 1-13.
[http://dx.doi.org/10.1042/BJ20070140] [PMID: 17447894 ] 
[2] 
D’Amours, D.; Desnoyers, S.; D’Silva, I.; Poirier, G.G. Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem. J.,  1999, 342(Pt 2), 249-268.
[http://dx.doi.org/10.1042/bj3420249] [PMID: 10455009 ] 
[3] 
Schreiber, V.; Dantzer, F.; Ame, J.C.; de Murcia, G. Poly(ADP-ribose): novel functions for an old molecule. Nat. Rev. Mol. Cell Biol.,  2006, 7(7), 517-528.
[http://dx.doi.org/10.1038/nrm1963] [PMID: 16829982 ] 
[4] 
Lee, H.C. Physiological functions of cyclic ADP-ribose and NAADP as calcium messengers. Annu. Rev. Pharmacol. Toxicol.,  2001, 41, 317-345.
[http://dx.doi.org/10.1146/annurev.pharmtox.41.1.317] [PMID: 11264460 ] 
[5] 
Lombard, D.B.; Chua, K.F.; Mostoslavsky, R.; Franco, S.; Gostissa, M.; Alt, F.W. DNA repair, genome stability, and aging. Cell,  2005, 120(4), 497-512.
[http://dx.doi.org/10.1016/j.cell.2005.01.028] [PMID: 15734682 ] 
[6] 
Blander, G.; Guarente, L. The Sir2 family of protein deacetylases. Annu. Rev. Biochem.,  2004, 73, 417-435.
[http://dx.doi.org/10.1146/annurev.biochem.73.011303.073651] [PMID: 15189148 ] 
[7] 
Hassa, P.O.; Haenni, S.S.; Elser, M.; Hottiger, M.O. Nuclear ADP-ribosylation reactions in mammalian cells: where are we today and where are we going? Microbiol. Mol. Biol. Rev.,  2006, 70(3), 789-829.
[http://dx.doi.org/10.1128/MMBR.00040-05] [PMID: 16959969 ] 
[8] 
Herceg, Z.; Wang, Z.Q. Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat. Res.,  2001, 477(1-2), 97-110.
[http://dx.doi.org/10.1016/S0027-5107(01)00111-7] [PMID: 11376691 ] 
[9] 
Kharechkina, E.S.; Nikiforova, A.B.; Teplova, V.V.; Odinokova, I.V.; Krestinina, O.V.; Baburina, Y.L.; Kruglova, S.A.; Kruglov, A.G. Regulation of permeability transition pore opening in mitochondria by external NAD(H). Biochim. Biophys. Acta, Gen. Subj.,  2019, 1863(5), 771-783.
[http://dx.doi.org/10.1016/j.bbagen.2019.01.003] [PMID: 30763605 ] 
[10] 
Rasola, A.; Bernardi, P. The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis. Apoptosis,  2007, 12(5), 815-833.
[http://dx.doi.org/10.1007/s10495-007-0723-y] [PMID: 17294078 ] 
[11] 
Kwong, J.Q.; Molkentin, J.D. Physiological and pathological roles of the mitochondrial permeability transition pore in the heart. Cell Metab.,  2015, 21(2), 206-214.
[http://dx.doi.org/10.1016/j.cmet.2014.12.001] [PMID: 25651175 ] 
[12] 
Hunter, D.R.; Haworth, R.A. The Ca2+-induced membrane transition in mitochondria. I. The protective mechanisms. Arch. Biochem. Biophys.,  1979, 195(2), 453-459.
[http://dx.doi.org/10.1016/0003-9861(79)90371-0] [PMID: 383019 ] 
[13] 
Haworth, R.A.; Hunter, D.R. Allosteric inhibition of the Ca2+-activated hydrophilic channel of the mitochondrial inner membrane by nucleotides. J. Membr. Biol.,  1980, 54(3), 231-236.
[http://dx.doi.org/10.1007/BF01870239] [PMID: 6248646 ] 
[14] 
Kurnasov, O.; Goral, V.; Colabroy, K.; Gerdes, S.; Anantha, S.; Osterman, A.; Begley, T.P. NAD biosynthesis: identification of the tryptophan to quinolinate pathway in bacteria. Chem. Biol.,  2003, 10(12), 1195-1204.
[http://dx.doi.org/10.1016/j.chembiol.2003.11.011] [PMID: 14700627 ] 
[15] 
Belenky, P.; Bogan, K.L.; Brenner, C. NAD+ metabolism in health and disease. Trends Biochem. Sci.,  2007, 32(1), 12-19.
[http://dx.doi.org/10.1016/j.tibs.2006.11.006] [PMID: 17161604 ] 
[16] 
Tempel, W.; Rabeh, W.M.; Bogan, K.L.; Belenky, P.; Wojcik, M.; Seidle, H.F.; Nedyalkova, L.; Yang, T.; Sauve, A.A.; Park, H.W.; Brenner, C. Nicotinamide riboside kinase structures reveal new pathways to NAD+. PLoS Biol.,  2007, 5(10), e263.
[http://dx.doi.org/10.1371/journal.pbio.0050263] [PMID: 17914902 ] 
[17] 
Schutz, G.; Feigelson, P. Purification and properties of rat liver tryptophan oxygenase. J. Biol. Chem.,  1972, 247(17), 5327-5332.
[http://dx.doi.org/10.1016/S0021-9258(20)81108-9] [PMID: 4626718 ] 
[18] 
Shimizu, T.; Nomiyama, S.; Hirata, F.; Hayaishi, O. Indoleamine 2,3-dioxygenase. Purification and some properties. J. Biol. Chem.,  1978, 253(13), 4700-4706.
[http://dx.doi.org/10.1016/S0021-9258(17)30447-7] [PMID: 26687] 
[19] 
Magni, G.; Amici, A.; Emanuelli, M.; Raffaelli, N.; Ruggieri, S. Enzymology of NAD+ synthesis. Adv. Enzymol. Relat. Areas Mol. Biol.,  1999, 73, 135-182, xi. [xi.].
[PMID: 10218108] 
[20] 
Nishizuka, Y.; Hayaishi, O. Enzymic synthesis of niacin nucleotides from 3-hydroxyanthranilic acid in mammalian liver. J. Biol. Chem.,  1963, 238, 483-485.
[http://dx.doi.org/10.1016/S0021-9258(19)84026-7] [PMID: 13938817] 
[21] 
Preiss, J.; Handler, P. Biosynthesis of diphosphopyridine nucleotide. I. Identification of intermediates. J. Biol. Chem.,  1958, 233(2), 488-492.
[http://dx.doi.org/10.1016/S0021-9258(18)64789-1] [PMID: 13563526 ] 
[22] 
Belenky, P.; Racette, F.G.; Bogan, K.L.; McClure, J.M.; Smith, J.S.; Brenner, C. Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell,  2007, 129(3), 473-484.
[http://dx.doi.org/10.1016/j.cell.2007.03.024] [PMID: 17482543 ] 
[23] 
Fletcher, R.S.; Ratajczak, J.; Doig, C.L.; Oakey, L.A.; Callingham, R.; Da Silva Xavier, G.; Garten, A.; Elhassan, Y.S.; Redpath, P.; Migaud, M.E.; Philp, A.; Brenner, C.; Canto, C.; Lavery, G.G. Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells. Mol. Metab.,  2017, 6(8), 819-832.
[http://dx.doi.org/10.1016/j.molmet.2017.05.011] [PMID: 28752046 ] 
[24] 
Tran, A.; Yokose, R.; Cen, Y. Chemo-enzymatic synthesis of isotopically labeled nicotinamide riboside. Org. Biomol. Chem.,  2018, 16(19), 3662-3671.
[http://dx.doi.org/10.1039/C8OB00552D] [PMID: 29714801 ] 
[25] 
Ratajczak, J.; Joffraud, M.; Trammell, S.A.; Ras, R.; Canela, N.; Boutant, M.; Kulkarni, S.S.; Rodrigues, M.; Redpath, P.; Migaud, M.E.; Auwerx, J.; Yanes, O.; Brenner, C.; Cantó, C. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat. Commun.,  2016, 7, 13103.
[http://dx.doi.org/10.1038/ncomms13103] [PMID: 27725675 ] 
[26] 
Trammell, S.A.; Schmidt, M.S.; Weidemann, B.J.; Redpath, P.; Jaksch, F.; Dellinger, R.W.; Li, Z.; Abel, E.D.; Migaud, M.E.; Brenner, C. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat. Commun.,  2016, 7, 12948.
[http://dx.doi.org/10.1038/ncomms12948] [PMID: 27721479 ] 
[27] 
Ryu, D.; Zhang, H.; Ropelle, E.R.; Sorrentino, V.; Mázala, D.A.; Mouchiroud, L.; Marshall, P.L.; Campbell, M.D.; Ali, A.S.; Knowels, G.M.; Bellemin, S.; Iyer, S.R.; Wang, X.; Gariani, K.; Sauve, A.A.; Cantó, C.; Conley, K.E.; Walter, L.; Lovering, R.M.; Chin, E.R.; Jasmin, B.J.; Marcinek, D.J.; Menzies, K.J.; Auwerx, J. NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation. Sci. Transl. Med.,  2016, 8(361), 361ra139.
[http://dx.doi.org/10.1126/scitranslmed.aaf5504] [PMID: 27798264 ] 
[28] 
Vaur, P.; Brugg, B.; Mericskay, M.; Li, Z.; Schmidt, M.S.; Vivien, D.; Orset, C.; Jacotot, E.; Brenner, C.; Duplus, E. Nicotinamide riboside, a form of vitamin B3, protects against excitotoxicity-induced axonal degeneration. FASEB J.,  2017, 31(12), 5440-5452.
[http://dx.doi.org/10.1096/fj.201700221RR] [PMID: 28842432 ] 
[29] 
Wu, L.E.; Sinclair, D.A. Restoring stem cells - all you need is NAD. Cell Res.,  2016, 26(9), 971-972.
[http://dx.doi.org/10.1038/cr.2016.80] [PMID: 27339086 ] 
[30] 
Camacho-Pereira, J.; Tarragó, M.G.; Chini, C.C.S.; Nin, V.; Escande, C.; Warner, G.M.; Puranik, A.S.; Schoon, R.A.; Reid, J.M.; Galina, A.; Chini, E.N. CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell Metab.,  2016, 23(6), 1127-1139.
[http://dx.doi.org/10.1016/j.cmet.2016.05.006] [PMID: 27304511 ] 
[31] 
Covarrubias, A.J.; Kale, A.; Perrone, R.; Lopez-Dominguez, J.A.; Pisco, A.O.; Kasler, H.G.; Schmidt, M.S.; Heckenbach, I.; Kwok, R.; Wiley, C.D.; Wong, H.S.; Gibbs, E.; Iyer, S.S.; Basisty, N.; Wu, Q.; Kim, I.J.; Silva, E.; Vitangcol, K.; Shin, K.O.; Lee, Y.M.; Riley, R.; Ben-Sahra, I.; Ott, M.; Schilling, B.; Scheibye-Knudsen, M.; Ishihara, K.; Quake, S.R.; Newman, J.; Brenner, C.; Campisi, J.; Verdin, E. Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. Nat Metab,  2020, 2(11), 1265-1283.
[http://dx.doi.org/10.1038/s42255-020-00305-3] [PMID: 33199924 ] 
[32] 
Massudi, H.; Grant, R.; Braidy, N.; Guest, J.; Farnsworth, B.; Guillemin, G.J. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One,  2012, 7(7), e42357.
[http://dx.doi.org/10.1371/journal.pone.0042357] [PMID: 22848760 ] 
[33] 
Cantó, C.; Auwerx, J. Caloric restriction, SIRT1 and longevity. Trends Endocrinol. Metab.,  2009, 20(7), 325-331.
[http://dx.doi.org/10.1016/j.tem.2009.03.008] [PMID: 19713122 ] 
[34] 
Cantó, C.; Jiang, L.Q.; Deshmukh, A.S.; Mataki, C.; Coste, A.; Lagouge, M.; Zierath, J.R.; Auwerx, J. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab.,  2010, 11(3), 213-219.
[http://dx.doi.org/10.1016/j.cmet.2010.02.006] [PMID: 20197054 ] 
[35] 
Cantó, C.; Auwerx, J. Targeting sirtuin 1 to improve metabolism: all you need is NAD.(+)? Pharmacol. Rev.,  2012, 64(1), 166-187.
[http://dx.doi.org/10.1124/pr.110.003905] [PMID: 22106091 ] 
[36] 
Cantó, C.; Houtkooper, R.H.; Pirinen, E.; Youn, D.Y.; Oosterveer, M.H.; Cen, Y.; Fernandez-Marcos, P.J.; Yamamoto, H.; Andreux, P.A.; Cettour-Rose, P.; Gademann, K.; Rinsch, C.; Schoonjans, K.; Sauve, A.A.; Auwerx, J. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab.,  2012, 15(6), 838-847.
[http://dx.doi.org/10.1016/j.cmet.2012.04.022] [PMID: 22682224 ] 
[37] 
Yoshino, J.; Mills, K.F.; Yoon, M.J.; Imai, S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab.,  2011, 14(4), 528-536.
[http://dx.doi.org/10.1016/j.cmet.2011.08.014] [PMID: 21982712 ] 
[38] 
Castro-Portuguez, R.; Sutphin, G.L. Kynurenine pathway, NAD+ synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan. Exp. Gerontol.,  2020, 132, 110841.
[http://dx.doi.org/10.1016/j.exger.2020.110841] [PMID: 31954874 ] 
[39] 
Phillips, R.S.; Iradukunda, E.C.; Hughes, T.; Bowen, J.P. Modulation of Enzyme Activity in the Kynurenine Pathway by Kynurenine Monooxygenase Inhibition. Front. Mol. Biosci.,  2019, 6(3), 3.
[http://dx.doi.org/10.3389/fmolb.2019.00003] [PMID: 30800661 ] 
[40] 
Yamazaki, F.; Kuroiwa, T.; Takikawa, O.; Kido, R. Human indolylamine 2,3-dioxygenase. Its tissue distribution, and characterization of the placental enzyme. Biochem. J.,  1985, 230(3), 635-638.
[http://dx.doi.org/10.1042/bj2300635] [PMID: 3877502] 
[41] 
Yuasa, H.J.; Sugiura, M.; Harumoto, T. A single amino acid residue regulates the substrate affinity and specificity of indoleamine 2,3-dioxygenase. Arch. Biochem. Biophys.,  2018, 640, 1-9.
[http://dx.doi.org/10.1016/j.abb.2017.12.019] [PMID: 29288638 ] 
[42] 
Hu, B.; Hissong, B.D.; Carlin, J.M. Interleukin-1 enhances indoleamine 2,3-dioxygenase activity by increasing specific mRNA expression in human mononuclear phagocytes. J. Interferon Cytokine Res.,  1995, 15(7), 617-624.
[http://dx.doi.org/10.1089/jir.1995.15.617] [PMID: 7553232 ] 
[43] 
Babcock, T.A.; Carlin, J.M. Transcriptional activation of indoleamine dioxygenase by interleukin 1 and tumor necrosis factor alpha in interferon-treated epithelial cells. Cytokine,  2000, 12(6), 588-594.
[http://dx.doi.org/10.1006/cyto.1999.0661] [PMID: 10843733 ] 
[44] 
Yoshida, R.; Hayaishi, O. Induction of pulmonary indoleamine 2,3-dioxygenase by intraperitoneal injection of bacterial lipopolysaccharide. Proc. Natl. Acad. Sci. USA,  1978, 75(8), 3998-4000.
[http://dx.doi.org/10.1073/pnas.75.8.3998] [PMID: 279015] 
[45] 
Muller, A.J.; DuHadaway, J.B.; Donover, P.S.; Sutanto-Ward, E.; Prendergast, G.C. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat. Med.,  2005, 11(3), 312-319.
[http://dx.doi.org/10.1038/nm1196] [PMID: 15711557 ] 
[46] 
Muller, A.J.; Malachowski, W.P.; Prendergast, G.C. Indoleamine 2,3-dioxygenase in cancer: targeting pathological immune tolerance with small-molecule inhibitors. Expert Opin. Ther. Targets,  2005, 9(4), 831-849.
[http://dx.doi.org/10.1517/14728222.9.4.831] [PMID: 16083346 ] 
[47] 
Cady, S.G.; Sono, M. 1-Methyl-DL-tryptophan, beta-(3-benzofuranyl)-DL-alanine (the oxygen analog of tryptophan), and beta-[3-benzo(b)thienyl]-DL-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase. Arch. Biochem. Biophys.,  1991, 291(2), 326-333.
[http://dx.doi.org/10.1016/0003-9861(91)90142-6] [PMID: 1952947 ] 
[48] 
Jackson, E.; Dees, E. C.; Kauh, J. S.; Harvey, R. D.; Neuger, A.; Lush, R.; Antonia, S. J.; Minton, S. E.; Ismail-Khan, R.; Han, H. S.; Vahanian, N. N.; Ramsey, W. J.; Link, C. J.; Streicher, H.; Sullivan, D.; Soliman, H. H. A phase I study of indoximod in combination with docetaxel in metastatic solid tumors. J. Clin. Onco.,  2013, 31(15_suppl), 3026-3026.
[http://dx.doi.org/10.1200/jco.2013.31.15_suppl.3026] 
[49] 
Jha, G. G.; Gupta, S.; Tagawa, S. T.; Koopmeiners, J. S.; Vivek, S.; Dudek, A. Z.; Cooley, S. A.; Blazar, B. R.; Miller, J. S. A phase II randomized, double-blind study of sipuleucel- T followed by IDO pathway inhibitor, indoximod, or placebo in the treatment of patients with metastatic castration resistant prostate cancer (mCRPC). J. Clin. Onco.,  2017, 35(15_suppl), 3066-3066.
[50] 
Zakharia, Y.; Rixe, O.; Ward, J. H.; Drabick, J. J.; Shaheen, M. F.; Milhem, M. M.; Munn, D.; Kennedy, E. P.; Vahanian, N. N.; Link, C. J.; McWilliams, R. R. Phase 2 trial of the IDO pathway inhibitor indoximod plus checkpoint inhibition for the treatment of patients with advanced melanoma. J. Clin. Onco.,  2018, 36(15_suppl), 9512-9512.
[http://dx.doi.org/10.1200/JCO.2018.36.15_suppl.9512] 
[51] 
Prendergast, G.C.; Metz, R. A perspective on new immune adjuvant principles: Reprogramming inflammatory states to permit clearance of cancer cells and other age-associated cellular pathologies. OncoImmunology,  2012, 1(6), 924-929.
[http://dx.doi.org/10.4161/onci.21358] [PMID: 23162760 ] 
[52] 
Yue, E.W.; Sparks, R.; Polam, P.; Modi, D.; Douty, B.; Wayland, B.; Glass, B.; Takvorian, A.; Glenn, J.; Zhu, W.; Bower, M.; Liu, X.; Leffet, L.; Wang, Q.; Bowman, K.J.; Hansbury, M.J.; Wei, M.; Li, Y.; Wynn, R.; Burn, T.C.; Koblish, H.K.; Fridman, J.S.; Emm, T.; Scherle, P.A.; Metcalf, B.; Combs, A.P. INCB24360 (Epacadostat), a highly potent and selective Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitor for Immuno-oncology. ACS Med. Chem. Lett.,  2017, 8(5), 486-491.
[http://dx.doi.org/10.1021/acsmedchemlett.6b00391] [PMID: 28523098 ] 
[53] 
Long, G.V.; Dummer, R.; Hamid, O.; Gajewski, T.F.; Caglevic, C.; Dalle, S.; Arance, A.; Carlino, M.S.; Grob, J.J.; Kim, T.M.; Demidov, L.; Robert, C.; Larkin, J.; Anderson, J.R.; Maleski, J.; Jones, M.; Diede, S.J.; Mitchell, T.C. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol.,  2019, 20(8), 1083-1097.
[http://dx.doi.org/10.1016/S1470-2045(19)30274-8] [PMID: 31221619 ] 
[54] 
Kumar, S.; Jaller, D.; Patel, B.; LaLonde, J.M.; DuHadaway, J.B.; Malachowski, W.P.; Prendergast, G.C.; Muller, A.J. Structure based development of phenylimidazole-derived inhibitors of indoleamine 2,3-dioxygenase. J. Med. Chem.,  2008, 51(16), 4968-4977.
[http://dx.doi.org/10.1021/jm800512z] [PMID: 18665584 ] 
[55] 
Röhrig, U.F.; Majjigapu, S.R.; Grosdidier, A.; Bron, S.; Stroobant, V.; Pilotte, L.; Colau, D.; Vogel, P.; Van den Eynde, B.J.; Zoete, V.; Michielin, O. Rational design of 4-aryl-1,2,3-triazoles for indoleamine 2,3-dioxygenase 1 inhibition. J. Med. Chem.,  2012, 55(11), 5270-5290.
[http://dx.doi.org/10.1021/jm300260v] [PMID: 22616902 ] 
[56] 
Mautino, M.R.; Jaipuri, F.A.; Waldo, J.; Kumar, S.; Adams, J.; Van Allen, C.; Marcinowicz-Flick, A.; Munn, D.; Vahanian, N.; Link, C.J. Abstract 491: NLG919, a novel indoleamine-2,3-dioxygenase (IDO)-pathway inhibitor drug candidate for cancer therapy. Cancer Res.,  2013, 73(8)(Suppl.), 491-491.
[57] 
Jung, K.H.; LoRusso, P.; Burris, H.; Gordon, M.; Bang, Y.J.; Hellmann, M.D.; Cervantes, A.; Ochoa de Olza, M.; Marabelle, A.; Hodi, F.S.; Ahn, M.J.; Emens, L.A.; Barlesi, F.; Hamid, O.; Calvo, E.; McDermott, D.; Soliman, H.; Rhee, I.; Lin, R.; Pourmohamad, T.; Suchomel, J.; Tsuhako, A.; Morrissey, K.; Mahrus, S.; Morley, R.; Pirzkall, A.; Davis, S.L.; Phase, I.; Phase, I. Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors. Clin. Cancer Res.,  2019, 25(11), 3220-3228.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-2740] [PMID: 30770348] 
[58] 
Yamamoto, N.; Fujiwara, Y.; Kondo, S.; Iwasa, S.; Yonemori, K.; Shimomura, A.; Kitano, S.; Shimizu, T.; Koyama, T.; Ebata, T.; Sato, N.; Nakai, K.; Inatani, M.; Tamura, K. Phase I study of IDO1 inhibitor navoximod (GDC-0919) as monotherapy and in combination with atezolizumab in Japanese patients with advanced solid tumors. Ann. Oncol.,  2018, 29(Suppl. 8), VIII138-VIII139.
[http://dx.doi.org/10.1093/annonc/mdy279.411 ] 
[59] 
Zwilling, D.; Huang, S.Y.; Sathyasaikumar, K.V.; Notarangelo, F.M.; Guidetti, P.; Wu, H.Q.; Lee, J.; Truong, J.; Andrews-Zwilling, Y.; Hsieh, E.W.; Louie, J.Y.; Wu, T.; Scearce-Levie, K.; Patrick, C.; Adame, A.; Giorgini, F.; Moussaoui, S.; Laue, G.; Rassoulpour, A.; Flik, G.; Huang, Y.; Muchowski, J.M.; Masliah, E.; Schwarcz, R.; Muchowski, P.J. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell,  2011, 145(6), 863-874.
[http://dx.doi.org/10.1016/j.cell.2011.05.020] [PMID: 21640374 ] 
[60] 
Perkins, M.N.; Stone, T.W. An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res.,  1982, 247(1), 184-187.
[http://dx.doi.org/10.1016/0006-8993(82)91048-4] [PMID: 6215086 ] 
[61] 
Hilmas, C.; Pereira, E.F.; Alkondon, M.; Rassoulpour, A.; Schwarcz, R.; Albuquerque, E.X. The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J. Neurosci.,  2001, 21(19), 7463-7473.
[http://dx.doi.org/10.1523/JNEUROSCI.21-19-07463.2001] [PMID: 11567036 ] 
[62] 
Okuda, S.; Nishiyama, N.; Saito, H.; Katsuki, H. Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine. Proc. Natl. Acad. Sci. USA,  1996, 93(22), 12553-12558.
[http://dx.doi.org/10.1073/pnas.93.22.12553] [PMID: 8901620 ] 
[63] 
Okuda, S.; Nishiyama, N.; Saito, H.; Katsuki, H. 3-Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity. J. Neurochem.,  1998, 70(1), 299-307.
[http://dx.doi.org/10.1046/j.1471-4159.1998.70010299.x] [PMID: 9422375 ] 
[64] 
Mole, D.J.; Webster, S.P.; Uings, I.; Zheng, X.; Binnie, M.; Wilson, K.; Hutchinson, J.P.; Mirguet, O.; Walker, A.; Beaufils, B.; Ancellin, N.; Trottet, L.; Bénéton, V.; Mowat, C.G.; Wilkinson, M.; Rowland, P.; Haslam, C.; McBride, A.; Homer, N.Z.; Baily, J.E.; Sharp, M.G.; Garden, O.J.; Hughes, J.; Howie, S.E.; Holmes, D.S.; Liddle, J.; Iredale, J.P. Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis. Nat. Med.,  2016, 22(2), 202-209.
[http://dx.doi.org/10.1038/nm.4020] [PMID: 26752518 ] 
[65] 
Pellicciari, R.; Natalini, B.; Costantino, G.; Mahmoud, M.R.; Mattoli, L.; Sadeghpour, B.M.; Moroni, F.; Chiarugi, A.; Carpenedo, R. Modulation of the kynurenine pathway in search for new neuroprotective agents. Synthesis and preliminary evaluation of (m-nitrobenzoyl)alanine, a potent inhibitor of kynurenine-3-hydroxylase. J. Med. Chem.,  1994, 37(5), 647-655.
[http://dx.doi.org/10.1021/jm00031a015] [PMID: 8126705 ] 
[66] 
Speciale, C.; Wu, H.Q.; Cini, M.; Marconi, M.; Varasi, M.; Schwarcz, R. (R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats. Eur. J. Pharmacol.,  1996, 315(3), 263-267.
[http://dx.doi.org/10.1016/S0014-2999(96)00613-9] [PMID: 8982663 ] 
[67] 
Pellicciari, R.; Amori, L.; Costantino, G.; Giordani, A.; Macchiarulo, A.; Mattoli, L.; Pevarello, P.; Speciale, C.; Varasi, M. Modulation of the kynurine pathway of tryptophan metabolism in search for neuroprotective agents. Focus on kynurenine-3-hydroxylase. Adv. Exp. Med. Biol.,  2003, 527, 621-628.
[http://dx.doi.org/10.1007/978-1-4615-0135-0_71] [PMID: 15206781 ] 
[68] 
Amaral, M.; Levy, C.; Heyes, D.J.; Lafite, P.; Outeiro, T.F.; Giorgini, F.; Leys, D.; Scrutton, N.S. Structural basis of kynurenine 3-monooxygenase inhibition. Nature,  2013, 496(7445), 382-385.
[http://dx.doi.org/10.1038/nature12039] [PMID: 23575632 ] 
[69] 
Röver, S.; Cesura, A.M.; Huguenin, P.; Kettler, R.; Szente, A. Synthesis and biochemical evaluation of N-(4-phenylthiazol-2-yl)benzenesulfonamides as high-affinity inhibitors of kynurenine 3-hydroxylase. J. Med. Chem.,  1997, 40(26), 4378-4385.
[http://dx.doi.org/10.1021/jm970467t] [PMID: 9435907 ] 
[70] 
Hutchinson, J.P.; Rowland, P.; Taylor, M.R.D.; Christodoulou, E.M.; Haslam, C.; Hobbs, C.I.; Holmes, D.S.; Homes, P.; Liddle, J.; Mole, D.J.; Uings, I.; Walker, A.L.; Webster, S.P.; Mowat, C.G.; Chung, C.W. Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase. Nat. Commun.,  2017, 8, 15827.
[http://dx.doi.org/10.1038/ncomms15827] [PMID: 28604669] 
[71] 
Pevarello, P.; Varasi, M.; Amici, R.; Toma, S.; Speciale, C. Tricyclic 3-oxo-propanenitrile Compounds. WO 1999/ 016753 A2 1999.
[72] 
Lowe, D.M.; Gee, M.; Haslam, C.; Leavens, B.; Christodoulou, E.; Hissey, P.; Hardwicke, P.; Argyrou, A.; Webster, S.P.; Mole, D.J.; Wilson, K.; Binnie, M.; Yard, B.A.; Dean, T.; Liddle, J.; Uings, I.; Hutchinson, J.P. Lead discovery for human kynurenine 3-monooxygenase by high-throughput RapidFire mass spectrometry. J. Biomol. Screen.,  2014, 19(4), 508-515.
[http://dx.doi.org/10.1177/1087057113518069] [PMID: 24381207 ] 
[73] 
Toledo-Sherman, L.M.; Prime, M.E.; Mrzljak, L.; Beconi, M.G.; Beresford, A.; Brookfield, F.A.; Brown, C.J.; Cardaun, I.; Courtney, S.M.; Dijkman, U.; Hamelin-Flegg, E.; Johnson, P.D.; Kempf, V.; Lyons, K.; Matthews, K.; Mitchell, W.L.; O’Connell, C.; Pena, P.; Powell, K.; Rassoulpour, A.; Reed, L.; Reindl, W.; Selvaratnam, S.; Friley, W.W.; Weddell, D.A.; Went, N.E.; Wheelan, P.; Winkler, C.; Winkler, D.; Wityak, J.; Yarnold, C.J.; Yates, D.; Munoz-Sanjuan, I.; Dominguez, C. Development of a series of aryl pyrimidine kynurenine monooxygenase inhibitors as potential therapeutic agents for the treatment of Huntington’s disease. J. Med. Chem.,  2015, 58(3), 1159-1183.
[http://dx.doi.org/10.1021/jm501350y] [PMID: 25590515 ] 
[74] 
Beaumont, V.; Mrzljak, L.; Dijkman, U.; Freije, R.; Heins, M.; Rassoulpour, A.; Tombaugh, G.; Gelman, S.; Bradaia, A.; Steidl, E.; Gleyzes, M.; Heikkinen, T.; Lehtimäki, K.; Puoliväli, J.; Kontkanen, O.; Javier, R.M.; Neagoe, I.; Deisemann, H.; Winkler, D.; Ebneth, A.; Khetarpal, V.; Toledo-Sherman, L.; Dominguez, C.; Park, L.C.; Munoz-Sanjuan, I. The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington’s disease. Exp. Neurol.,  2016, 282, 99-118.
[http://dx.doi.org/10.1016/j.expneurol.2016.05.005] [PMID: 27163548 ] 
[75] 
Phillips, R.S. Structure and mechanism of kynureninase. Arch. Biochem. Biophys.,  2014, 544, 69-74.
[http://dx.doi.org/10.1016/j.abb.2013.10.020] [PMID: 24200862 ] 
[76] 
Lima, S.; Kumar, S.; Gawandi, V.; Momany, C.; Phillips, R.S. Crystal structure of the Homo sapiens kynureninase-3-hydroxyhippuric acid inhibitor complex: insights into the molecular basis of kynureninase substrate specificity. J. Med. Chem.,  2009, 52(2), 389-396.
[http://dx.doi.org/10.1021/jm8010806] [PMID: 19143568 ] 
[77] 
Phillips, R.S.; Dua, R.K. Stereochemistry and mechanism of aldol reactions catalyzed by kynureninase. J. Am. Chem. Soc.,  1991, 113(19), 7385-7388.
[http://dx.doi.org/10.1021/ja00019a039] 
[78] 
Dua, R.K.; Taylor, E.W.; Phillips, R.S. S-Aryl-L-cysteine S,S-dioxides: design, synthesis, and evaluation of a new class of inhibitors of kynureninase. J. Am. Chem. Soc.,  1993, 115(4), 1264-1270.
[http://dx.doi.org/10.1021/ja00057a007] 
[79] 
Ross, F.C.; Botting, N.P.; Leeson, P.D. Synthesis of phosphinic acid transition state analogues for the reaction catalysed by kynureninase. Bioorg. Med. Chem. Lett.,  1996, 6(22), 2643-2646.
[http://dx.doi.org/10.1016/S0960-894X(96)00483-0] 
[80] 
Walsh, H.A.; Leslie, P.L.; O’Shea, K.C.; Botting, N.P. 2-Amino-4-[3′-hydroxyphenyl]-4-hydroxybutanoic acid; a potent inhibitor of rat and recombinant human kynureninase. Bioorg. Med. Chem. Lett.,  2002, 12(3), 361-363.
[http://dx.doi.org/10.1016/S0960-894X(01)00758-2] [PMID: 11814797 ] 
[81] 
Iwai, K.; Taguchi, H. Distribution of quinolinate phosphoribosyl-transferase in animals, plants and microorganisms. J. Nutr. Sci. Vitaminol. (Tokyo),  1973, 19(6), 491-499.
[http://dx.doi.org/10.3177/jnsv.19.491] [PMID: 4799479 ] 
[82] 
Buonvicino, D.; Mazzola, F.; Zamporlini, F.; Resta, F.; Ranieri, G.; Camaioni, E.; Muzzi, M.; Zecchi, R.; Pieraccini, G.; Dolle, C.; Calamante, M.; Bartolucci, G.; Ziegler, M.; Stecca, B.; Raffaelli, N.; Chiarugi, A. Identification of the nicotinamide salvage pathway as a new toxification route for antimetabolites.  Cell Chem Biol,,  2018, 25(4), 471-482., e7.
[http://dx.doi.org/10.1016/j.chembiol.2018.01.012] 
[83] 
Sahm, F.; Oezen, I.; Opitz, C.A.; Radlwimmer, B.; von Deimling, A.; Ahrendt, T.; Adams, S.; Bode, H.B.; Guillemin, G.J.; Wick, W.; Platten, M. The endogenous tryptophan metabolite and NAD+ precursor quinolinic acid confers resistance of gliomas to oxidative stress. Cancer Res.,  2013, 73(11), 3225-3234.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-3831] [PMID: 23548271 ] 
[84] 
Malik, S.S.; Patterson, D.N.; Ncube, Z.; Toth, E.A. The crystal structure of human quinolinic acid phosphoribosyltransferase in complex with its inhibitor phthalic acid. Proteins,  2014, 82(3), 405-414.
[http://dx.doi.org/10.1002/prot.24406] [PMID: 24038671 ] 
[85] 
Braidy, N.; Guillemin, G.J.; Grant, R. Effects of Kynurenine Pathway Inhibition on NAD Metabolism and Cell Viability in Human Primary Astrocytes and Neurons. Int. J. Tryptophan Res.,  2011, 4, 29-37.
[http://dx.doi.org/10.4137/IJTR.S7052] [PMID: 22084601 ] 
[86] 
Berger, F.; Lau, C.; Dahlmann, M.; Ziegler, M. Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms. J. Biol. Chem.,  2005, 280(43), 36334-36341.
[http://dx.doi.org/10.1074/jbc.M508660200] [PMID: 16118205 ] 
[87] 
Liu, X.; Liu, M.; Tang, C.; Xiang, Z.; Li, Q.; Ruan, X.; Xiong, K.; Zheng, L. Overexpression of Nmnat improves the adaption of health span in aging Drosophila. Exp. Gerontol.,  2018, 108, 276-283.
[http://dx.doi.org/10.1016/j.exger.2018.04.026] [PMID: 29727704 ] 
[88] 
Gulshan, M.; Yaku, K.; Okabe, K.; Mahmood, A.; Sasaki, T.; Yamamoto, M.; Hikosaka, K.; Usui, I.; Kitamura, T.; Tobe, K.; Nakagawa, T. Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age-associated insulin resistance. Aging Cell,  2018, 17(4), e12798.
[http://dx.doi.org/10.1111/acel.12798] [PMID: 29901258 ] 
[89] 
Anderson, R.M.; Bitterman, K.J.; Wood, J.G.; Medvedik, O.; Cohen, H.; Lin, S.S.; Manchester, J.K.; Gordon, J.I.; Sinclair, D.A. Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levels. J. Biol. Chem.,  2002, 277(21), 18881-18890.
[http://dx.doi.org/10.1074/jbc.M111773200] [PMID: 11884393 ] 
[90] 
Ali, Y.O.; Li-Kroeger, D.; Bellen, H.J.; Zhai, R.G.; Lu, H.C. NMNATs, evolutionarily conserved neuronal maintenance factors. Trends Neurosci.,  2013, 36(11), 632-640.
[http://dx.doi.org/10.1016/j.tins.2013.07.002] [PMID: 23968695 ] 
[91] 
Yahata, N.; Yuasa, S.; Araki, T. Nicotinamide mononucleotide adenylyltransferase expression in mitochondrial matrix delays Wallerian degeneration. J. Neurosci.,  2009, 29(19), 6276-6284.
[http://dx.doi.org/10.1523/JNEUROSCI.4304-08.2009] [PMID: 19439605 ] 
[92] 
Tang, B.L. Why is NMNAT Protective against Neuronal Cell Death and Axon Degeneration, but Inhibitory of Axon Regeneration? Cells,  2019, 8(3), E267.
[http://dx.doi.org/10.3390/cells8030267] [PMID: 30901919 ] 
[93] 
Cui, C.; Qi, J.; Deng, Q.; Chen, R.; Zhai, D.; Yu, J. Nicotinamide Mononucleotide Adenylyl Transferase 2: A promising diagnostic and therapeutic target for colorectal cancer. BioMed Res. Int.,  2016, 2016, 1804137.
[http://dx.doi.org/10.1155/2016/1804137] [PMID: 27218101 ] 
[94] 
Pan, L.Z.; Ahn, D.G.; Sharif, T.; Clements, D.; Gujar, S.A.; Lee, P.W. The NAD+ synthesizing enzyme nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2) is a p53 downstream target. Cell Cycle,  2014, 13(6), 1041-1048.
[http://dx.doi.org/10.4161/cc.28128] [PMID: 24552824 ] 
[95] 
Li, H.; Feng, Z.; Wu, W.; Li, J.; Zhang, J.; Xia, T. SIRT3 regulates cell proliferation and apoptosis related to energy metabolism in non-small cell lung cancer cells through deacetylation of NMNAT2. Int. J. Oncol.,  2013, 43(5), 1420-1430.
[http://dx.doi.org/10.3892/ijo.2013.2103] [PMID: 24042441 ] 
[96] 
Imai, S. Nicotinamide phosphoribosyltransferase (Nampt): a link between NAD biology, metabolism, and diseases. Curr. Pharm. Des.,  2009, 15(1), 20-28.
[http://dx.doi.org/10.2174/138161209787185814] [PMID: 19149599 ] 
[97] 
Samal, B.; Sun, Y.; Stearns, G.; Xie, C.; Suggs, S.; McNiece, I. Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor. Mol. Cell. Biol.,  1994, 14(2), 1431-1437.
[http://dx.doi.org/10.1128/MCB.14.2.1431] [PMID: 8289818  ] 
[98] 
Fukuhara, A.; Matsuda, M.; Nishizawa, M.; Segawa, K.; Tanaka, M.; Kishimoto, K.; Matsuki, Y.; Murakami, M.; Ichisaka, T.; Murakami, H.; Watanabe, E.; Takagi, T.; Akiyoshi, M.; Ohtsubo, T.; Kihara, S.; Yamashita, S.; Makishima, M.; Funahashi, T.; Yamanaka, S.; Hiramatsu, R.; Matsuzawa, Y.; Shimomura, I. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science,  2005, 307(5708), 426-430.
[http://dx.doi.org/10.1126/science.1097243] [PMID: 15604363] 
[99] 
Revollo, J.R.; Körner, A.; Mills, K.F.; Satoh, A.; Wang, T.; Garten, A.; Dasgupta, B.; Sasaki, Y.; Wolberger, C.; Townsend, R.R.; Milbrandt, J.; Kiess, W.; Imai, S. Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell Metab.,  2007, 6(5), 363-375.
[http://dx.doi.org/10.1016/j.cmet.2007.09.003] [PMID: 17983582 ] 
[100] 
Reddy, P.S.; Umesh, S.; Thota, B.; Tandon, A.; Pandey, P.; Hegde, A.S.; Balasubramaniam, A.; Chandramouli, B.A.; Santosh, V.; Rao, M.R.; Kondaiah, P.; Somasundaram, K. PBEF1/NAmPRTase/Visfatin: a potential malignant astrocytoma/glioblastoma serum marker with prognostic value. Cancer Biol. Ther.,  2008, 7(5), 663-668.
[http://dx.doi.org/10.4161/cbt.7.5.5663] [PMID: 18728403 ] 
[101] 
Maldi, E.; Travelli, C.; Caldarelli, A.; Agazzone, N.; Cintura, S.; Galli, U.; Scatolini, M.; Ostano, P.; Miglino, B.; Chiorino, G.; Boldorini, R.; Genazzani, A.A. Nicotinamide phosphoribosyltransferase (NAMPT) is over-expressed in melanoma lesions. Pigment Cell Melanoma Res.,  2013, 26(1), 144-146.
[http://dx.doi.org/10.1111/pcmr.12037] [PMID: 23051650 ] 
[102] 
Olesen, U.H.; Hastrup, N.; Sehested, M. Expression patterns of nicotinamide phosphoribosyltransferase and nicotinic acid phosphoribosyltransferase in human malignant lymphomas. APMIS,  2011, 119(4-5), 296-303.
[http://dx.doi.org/10.1111/j.1600-0463.2011.02733.x] [PMID: 21492230 ] 
[103] 
Galli, U.; Travelli, C.; Massarotti, A.; Fakhfouri, G.; Rahimian, R.; Tron, G.C.; Genazzani, A.A. Medicinal chemistry of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. J. Med. Chem.,  2013, 56(16), 6279-6296.
[http://dx.doi.org/10.1021/jm4001049] [PMID: 23679915 ] 
[104] 
Sampath, D.; Zabka, T.S.; Misner, D.L.; O’Brien, T.; Dragovich, P.S. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) as a therapeutic strategy in cancer. Pharmacol. Ther.,  2015, 151, 16-31.
[http://dx.doi.org/10.1016/j.pharmthera.2015.02.004] [PMID: 25709099] 
[105] 
Wosikowski, K.; Mattern, K.; Schemainda, I.; Hasmann, M.; Rattel, B.; Löser, R. WK175, a novel antitumor agent, decreases the intracellular nicotinamide adenine dinucleotide concentration and induces the apoptotic cascade in human leukemia cells. Cancer Res.,  2002, 62(4), 1057-1062.
[PMID: 11861382] 
[106] 
Hasmann, M.; Schemainda, I. FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. Cancer Res.,  2003, 63(21), 7436-7442.
[PMID: 14612543 ] 
[107] 
Goldinger, S.M.; Gobbi Bischof, S.; Fink-Puches, R.; Klemke, C.D.; Dréno, B.; Bagot, M.; Dummer, R. Efficacy and Safety of APO866 in Patients With Refractory or Relapsed Cutaneous T-Cell Lymphoma: A Phase 2 Clinical Trial. JAMA Dermatol.,  2016, 152(7), 837-839.
[http://dx.doi.org/10.1001/jamadermatol.2016.0401] [PMID: 27007550 ] 
[108] 
Olesen, U.H.; Christensen, M.K.; Björkling, F.; Jäättelä, M.; Jensen, P.B.; Sehested, M.; Nielsen, S.J. Anticancer agent CHS-828 inhibits cellular synthesis of NAD. Biochem. Biophys. Res. Commun.,  2008, 367(4), 799-804.
[http://dx.doi.org/10.1016/j.bbrc.2008.01.019] [PMID: 18201551 ] 
[109] 
Watson, M.; Roulston, A.; Bélec, L.; Billot, X.; Marcellus, R.; Bédard, D.; Bernier, C.; Branchaud, S.; Chan, H.; Dairi, K.; Gilbert, K.; Goulet, D.; Gratton, M.O.; Isakau, H.; Jang, A.; Khadir, A.; Koch, E.; Lavoie, M.; Lawless, M.; Nguyen, M.; Paquette, D.; Turcotte, E.; Berger, A.; Mitchell, M.; Shore, G.C.; Beauparlant, P. The small molecule GMX1778 is a potent inhibitor of NAD+ biosynthesis: strategy for enhanced therapy in nicotinic acid phosphoribosyltransferase 1-deficient tumors. Mol. Cell. Biol.,  2009, 29(21), 5872-5888.
[http://dx.doi.org/10.1128/MCB.00112-09] [PMID: 19703994 ] 
[110] 
Beauparlant, P.; Bédard, D.; Bernier, C.; Chan, H.; Gilbert, K.; Goulet, D.; Gratton, M.O.; Lavoie, M.; Roulston, A.; Turcotte, E.; Watson, M. Preclinical development of the nicotinamide phosphoribosyl transferase inhibitor prodrug GMX1777. Anticancer Drugs,  2009, 20(5), 346-354.
[http://dx.doi.org/10.1097/CAD.0b013e3283287c20] [PMID: 19369827 ] 
[111] 
You, H.; Youn, H.S. Im, I.; Bae, M.H.; Lee, S.K.; Ko, H.; Eom, S.H.; Kim, Y.C. Design, synthesis and X-ray crystallographic study of NAmPRTase inhibitors as anti-cancer agents. Eur. J. Med. Chem.,  2011, 46(4), 1153-1164.
[http://dx.doi.org/10.1016/j.ejmech.2011.01.034] [PMID: 21330015 ] 
[112] 
Gunzner-Toste, J.; Zhao, G.; Bauer, P.; Baumeister, T.; Buckmelter, A.J.; Caligiuri, M.; Clodfelter, K.H.; Fu, B.; Han, B.; Ho, Y.C.; Kley, N.; Liang, X.; Liederer, B.M.; Lin, J.; Mukadam, S.; O’Brien, T.; Oh, A.; Reynolds, D.J.; Sharma, G.; Skelton, N.; Smith, C.C.; Sodhi, J.; Wang, W.; Wang, Z.; Xiao, Y.; Yuen, P.W.; Zak, M.; Zhang, L.; Zheng, X.; Bair, K.W.; Dragovich, P.S. Discovery of potent and efficacious urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with reduced CYP2C9 inhibition properties. Bioorg. Med. Chem. Lett.,  2013, 23(12), 3531-3538.
[http://dx.doi.org/10.1016/j.bmcl.2013.04.040] [PMID: 23668988 ] 
[113] 
Zheng, X.; Bauer, P.; Baumeister, T.; Buckmelter, A.J.; Caligiuri, M.; Clodfelter, K.H.; Han, B.; Ho, Y.C.; Kley, N.; Lin, J.; Reynolds, D.J.; Sharma, G.; Smith, C.C.; Wang, Z.; Dragovich, P.S.; Oh, A.; Wang, W.; Zak, M.; Gunzner-Toste, J.; Zhao, G.; Yuen, P.W.; Bair, K.W. Structure-based identification of ureas as novel nicotinamide phosphoribosyltransferase (Nampt) inhibitors. J. Med. Chem.,  2013, 56(12), 4921-4937.
[http://dx.doi.org/10.1021/jm400186h] [PMID: 23617784 ] 
[114] 
Colombano, G.; Travelli, C.; Galli, U.; Caldarelli, A.; Chini, M.G.; Canonico, P.L.; Sorba, G.; Bifulco, G.; Tron, G.C.; Genazzani, A.A. A novel potent nicotinamide phosphoribosyltransferase inhibitor synthesized via click chemistry. J. Med. Chem.,  2010, 53(2), 616-623.
[http://dx.doi.org/10.1021/jm9010669] [PMID: 19961183 ] 
[115] 
Xu, T.Y.; Zhang, S.L.; Dong, G.Q.; Liu, X.Z.; Wang, X.; Lv, X.Q.; Qian, Q.J.; Zhang, R.Y.; Sheng, C.Q.; Miao, C.Y. Discovery and characterization of novel small-molecule inhibitors targeting nicotinamide phosphoribosyltransferase. Sci. Rep.,  2015, 5, 10043.
[http://dx.doi.org/10.1038/srep10043] [PMID: 26040985 ] 
[116] 
Estoppey, D.; Hewett, J.W.; Guy, C.T.; Harrington, E.; Thomas, J.R.; Schirle, M.; Cuttat, R.; Waldt, A.; Gerrits, B.; Yang, Z.; Schuierer, S.; Pan, X.; Xie, K.; Carbone, W.; Knehr, J.; Lindeman, A.; Russ, C.; Frias, E.; Hoffman, G.R.; Varadarajan, M.; Ramadan, N.; Reece-Hoyes, J.S.; Wang, Q.; Chen, X.; McAllister, G.; Roma, G.; Bouwmeester, T.; Hoepfner, D. Identification of a novel NAMPT inhibitor by CRISPR/Cas9 chemogenomic profiling in mammalian cells. Sci. Rep.,  2017, 7, 42728.
[http://dx.doi.org/10.1038/srep42728] [PMID: 28205648 ] 
[117] 
Fleischer, T.C.; Murphy, B.R.; Flick, J.S.; Terry-Lorenzo, R.T.; Gao, Z.H.; Davis, T.; McKinnon, R.; Ostanin, K.; Willardsen, J.A.; Boniface, J.J. Chemical proteomics identifies Nampt as the target of CB30865, an orphan cytotoxic compound. Chem. Biol.,  2010, 17(6), 659-664.
[http://dx.doi.org/10.1016/j.chembiol.2010.05.008] [PMID: 20609415 ] 
[118] 
Oh, A.; Ho, Y.C.; Zak, M.; Liu, Y.; Chen, X.; Yuen, P.W.; Zheng, X.; Liu, Y.; Dragovich, P.S.; Wang, W. Structural and biochemical analyses of the catalysis and potency impact of inhibitor phosphoribosylation by human nicotinamide phosphoribosyltransferase. ChemBioChem,  2014, 15(8), 1121-1130.
[http://dx.doi.org/10.1002/cbic.201402023] [PMID: 24797455 ] 
[119] 
Lee, M.W., Jr; Sevryugina, Y.V.; Khan, A.; Ye, S.Q. Carboranes increase the potency of small molecule inhibitors of nicotinamide phosphoribosyltranferase. J. Med. Chem.,  2012, 55(16), 7290-7294.
[http://dx.doi.org/10.1021/jm300740t] [PMID: 22889195 ] 
[120] 
Korepanova, A.; Longenecker, K.L.; Pratt, S.D.; Panchal, S.C.; Clark, R.F.; Lake, M.; Gopalakrishnan, S.M.; Raich, D.; Sun, C.; Petros, A.M. Fragment-based discovery of a potent NAMPT inhibitor. Bioorg. Med. Chem. Lett.,  2018, 28(3), 437-440.
[http://dx.doi.org/10.1016/j.bmcl.2017.12.023] [PMID: 29287958 ] 
[121] 
Korotchkina, L.; Kazyulkin, D.; Komarov, P.G.; Polinsky, A.; Andrianova, E.L.; Joshi, S.; Gupta, M.; Vujcic, S.; Kononov, E.; Toshkov, I.; Tian, Y.; Krasnov, P.; Chernov, M.V.; Veith, J.; Antoch, M.P.; Middlemiss, S.; Somers, K.; Lock, R.B.; Norris, M.D.; Henderson, M.J.; Haber, M.; Chernova, O.B.; Gudkov, A.V. OT-82, a novel anticancer drug candidate that targets the strong dependence of hematological malignancies on NAD biosynthesis. Leukemia,  2020, 34(7), 1828-1839.
[http://dx.doi.org/10.1038/s41375-019-0692-5] [PMID: 31896781 ] 
[122] 
Talevi, A. Multi-target pharmacology: possibilities and limitations of the “skeleton key approach” from a medicinal chemist perspective. Front. Pharmacol.,  2015, 6, 205.
[http://dx.doi.org/10.3389/fphar.2015.00205] [PMID: 26441661 ] 
[123] 
Zimmermann, G.R.; Lehár, J.; Keith, C.T. Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discov. Today,  2007, 12(1-2), 34-42.
[http://dx.doi.org/10.1016/j.drudis.2006.11.008] [PMID: 17198971 ] 
[124] 
Abu Aboud, O.; Chen, C.H.; Senapedis, W.; Baloglu, E.; Argueta, C.; Weiss, R.H. Dual and Specific Inhibition of NAMPT and PAK4 By KPT-9274 Decreases Kidney Cancer Growth. Mol. Cancer Ther.,  2016, 15(9), 2119-2129.
[http://dx.doi.org/10.1158/1535-7163.MCT-16-0197] [PMID: 27390344 ] 
[125] 
Kraus, D.; Reckenbeil, J.; Veit, N.; Kuerpig, S.; Meisenheimer, M.; Beier, I.; Stark, H.; Winter, J.; Probstmeier, R. Targeting glucose transport and the NAD pathway in tumor cells with STF-31: a re-evaluation. Cell Oncol. (Dordr.),  2018, 41(5), 485-494.
[http://dx.doi.org/10.1007/s13402-018-0385-5] [PMID: 29949049 ] 
[126] 
Dong, G.; Chen, W.; Wang, X.; Yang, X.; Xu, T.; Wang, P.; Zhang, W.; Rao, Y.; Miao, C.; Sheng, C. Small Molecule Inhibitors Simultaneously Targeting Cancer Metabolism and Epigenetics: Discovery of Novel Nicotinamide Phosphoribosyltransferase (NAMPT) and Histone Deacetylase (HDAC) Dual Inhibitors. J. Med. Chem.,  2017, 60(19), 7965-7983.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00467] [PMID: 28885834 ] 
[127] 
Chen, W.; Dong, G.; Wu, Y.; Zhang, W.; Miao, C.; Sheng, C. Dual NAMPT/HDAC Inhibitors as a New Strategy for Multitargeting Antitumor Drug Discovery. ACS Med. Chem. Lett.,  2017, 9(1), 34-38.
[http://dx.doi.org/10.1021/acsmedchemlett.7b00414] [PMID: 29348808 ] 
[128] 
Pieper, A.A.; Xie, S.; Capota, E.; Estill, S.J.; Zhong, J.; Long, J.M.; Becker, G.L.; Huntington, P.; Goldman, S.E.; Shen, C-H.; Capota, M.; Britt, J.K.; Kotti, T.; Ure, K.; Brat, D.J.; Williams, N.S.; MacMillan, K.S.; Naidoo, J.; Melito, L.; Hsieh, J.; De Brabander, J.; Ready, J.M.; McKnight, S.L. Discovery of a proneurogenic, neuroprotective chemical. Cell,  2010, 142(1), 39-51.
[http://dx.doi.org/10.1016/j.cell.2010.06.018] [PMID: 20603013 ] 
[129] 
Wang, G.; Han, T.; Nijhawan, D.; Theodoropoulos, P.; Naidoo, J.; Yadavalli, S.; Mirzaei, H.; Pieper, A.A.; Ready, J.M.; McKnight, S.L. P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. Cell,  2014, 158(6), 1324-1334.
[http://dx.doi.org/10.1016/j.cell.2014.07.040] [PMID: 25215490 ] 
[130] 
Gardell, S.J.; Hopf, M.; Khan, A.; Dispagna, M.; Hampton Sessions, E.; Falter, R.; Kapoor, N.; Brooks, J.; Culver, J.; Petucci, C.; Ma, C-T.; Cohen, S.E.; Tanaka, J.; Burgos, E.S.; Hirschi, J.S.; Smith, S.R.; Sergienko, E.; Pinkerton, A.B.; Boosting, N.A.D. Boosting NAD+ with a small molecule that activates NAMPT. Nat. Commun.,  2019, 10(1), 3241.
[http://dx.doi.org/10.1038/s41467-019-11078-z] [PMID: 31324777 ] 
[131] 
Duarte-Pereira, S.; Pereira-Castro, I.; Silva, S.S.; Correia, M.G.; Neto, C.; da Costa, L.T.; Amorim, A.; Silva, R.M. Extensive regulation of nicotinate phosphoribosyltransferase (NAPRT) expression in human tissues and tumors. Oncotarget,  2016, 7(2), 1973-1983.
[http://dx.doi.org/10.18632/oncotarget.6538] [PMID: 26675378 ] 
[132] 
Piacente, F.; Caffa, I.; Ravera, S.; Sociali, G.; Passalacqua, M.; Vellone, V.G.; Becherini, P.; Reverberi, D.; Monacelli, F.; Ballestrero, A.; Odetti, P.; Cagnetta, A.; Cea, M.; Nahimana, A.; Duchosal, M.; Bruzzone, S.; Nencioni, A. Nicotinic Acid Phosphoribosyltransferase Regulates Cancer Cell Metabolism, Susceptibility to NAMPT Inhibitors, and DNA Repair. Cancer Res.,  2017, 77(14), 3857-3869.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-3079] [PMID: 28507103 ] 
[133] 
Li, X.Q.; Lei, J.; Mao, L.H.; Wang, Q.L.; Xu, F.; Ran, T.; Zhou, Z.H.; He, S. NAMPT and NAPRT, Key Enzymes in NAD Salvage Synthesis Pathway, Are of Negative Prognostic Value in Colorectal Cancer. Front. Oncol.,  2019, 9, 736.
[http://dx.doi.org/10.3389/fonc.2019.00736] [PMID: 31448236 ] 
[134] 
Marletta, A.S.; Massarotti, A.; Orsomando, G.; Magni, G.; Rizzi, M.; Garavaglia, S. Crystal structure of human nicotinic acid phosphoribosyltransferase. FEBS Open Bio,  2015, 5, 419-428.
[http://dx.doi.org/10.1016/j.fob.2015.05.002] [PMID: 26042198] 
[135] 
Khan, J.A.; Tao, X.; Tong, L. Molecular basis for the inhibition of human NMPRTase, a novel target for anticancer agents. Nat. Struct. Mol. Biol.,  2006, 13(7), 582-588.
[http://dx.doi.org/10.1038/nsmb1105] [PMID: 16783377 ] 
[136] 
Gaut, Z.N.; Solomon, H.M. Inhibition of nicotinate phosphoribosyltransferase in human platelet lysate by nicotinic acid analogs. Biochem. Pharmacol.,  1971, 20(10), 2903-2906.
[http://dx.doi.org/10.1016/0006-2952(71)90202-4] [PMID: 4255930 ] 
[137] 
Gaut, Z.N.; Solomon, H.M. Inhibition of nicotinate phosphoribosyl transferase by nonsteroidal anti-inflammatory drugs: a possible mechanism of action. J. Pharm. Sci.,  1971, 60(12), 1887-1888.
[http://dx.doi.org/10.1002/jps.2600601230] [PMID: 4333776 ] 
[138] 
Johnson, S.; Imai, S.I. NAD + biosynthesis, aging, and disease. F1000 Res.,  2018, 7, 132.
[http://dx.doi.org/10.12688/f1000research.12120.1] [PMID: 29744033 ] 
[139] 
Yang, Y.; Sauve, A.A. NAD(+) metabolism: Bioenergetics, signaling and manipulation for therapy. Biochim. Biophys. Acta,  2016, 1864(12), 1787-1800.
[http://dx.doi.org/10.1016/j.bbapap.2016.06.014] [PMID: 27374990 ] 
[140] 
Yaku, K.; Okabe, K.; Nakagawa, T. NAD metabolism: Implications in aging and longevity. Ageing Res. Rev.,  2018, 47, 1-17.
[http://dx.doi.org/10.1016/j.arr.2018.05.006] [PMID: 29883761 ] 
[141] 
Imai, S.I. The NAD World 2.0: the importance of the inter-tissue communication mediated by NAMPT/NAD+/SIRT1 in mammalian aging and longevity control. NPJ Syst. Biol. Appl.,  2016, 2, 16018.
[http://dx.doi.org/10.1038/npjsba.2016.18] [PMID: 28725474 ] 
[142] 
Qian, S.; Zhang, M.; Chen, Q.L.; He, Y.Y.; Wang, W.; Wang, Z.Y. IDO as a drug target for cancer immunotherapy: recent developments in IDO inhibitors discovery. RSC Advances,  2016, 6(9), 7575-7581.
[http://dx.doi.org/10.1039/C5RA25046C] 
[143] 
Houtkooper, R.H.; Cantó, C.; Wanders, R.J.; Auwerx, J. The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr. Rev.,  2010, 31(2), 194-223.
[http://dx.doi.org/10.1210/er.2009-0026] [PMID: 20007326 ] 
[144] 
Hong, W.; Mo, F.; Zhang, Z.; Huang, M.; Wei, X. Nicotinamide Mononucleotide: A Promising Molecule for Therapy of Diverse Diseases by Targeting NAD+ Metabolism. Front. Cell Dev. Biol.,  2020, 8, 246.
[http://dx.doi.org/10.3389/fcell.2020.00246] [PMID: 32411700 ] 
[145] 
Bertoldo, M. J.; Listijono, D. R.; Ho, W. J.; Riepsamen, A. H.; Goss, D. M.; Richani, D.; Jin, X. L.; Mahbub, S.; Campbell, J. M.; Habibalahi, A.; Loh, W. N.; Youngson, N. A.; Maniam, J.; Wong, A. S. A.; Selesniemi, K.; Bustamante, S.; Li, C.; Zhao, Y.; Marinova, M. B.; Kim, L. J.; Lau, L.; Wu, R. M.; Mikolaizak, A. S.; Araki, T.; Le Couteur, D. G.; Turner, N.; Morris, M. J.; Walters, K. A.; Goldys, E.; O'Neill, C.; Gilchrist, R. B.; Sinclair, D. A.; Homer, H. A.; Wu, L. E. NAD(+) Repletion Rescues Female Fertility during Reproductive Aging.		 Cell Rep,  2020, 30(6), 1670-1681., e7.
[146] 
Billington, R.A.; Travelli, C.; Ercolano, E.; Galli, U.; Roman, C.B.; Grolla, A.A.; Canonico, P.L.; Condorelli, F.; Genazzani, A.A. Characterization of NAD uptake in mammalian cells. J. Biol. Chem.,  2008, 283(10), 6367-6374.
[http://dx.doi.org/10.1074/jbc.M706204200] [PMID: 18180302 ] 
[147] 
Zhang, S.L.; Xu, T.Y.; Yang, Z.L.; Han, S.; Zhao, Q.; Miao, C.Y. Crystal structure-based comparison of two NAMPT inhibitors. Acta Pharmacol. Sin.,  2018, 39(2), 294-301.
[http://dx.doi.org/10.1038/aps.2017.80] [PMID: 28858298 ] 
[148] 
Skelton, L.A.; Ormerod, M.G.; Titley, J.C.; Jackman, A.L. Cell cycle effects of CB30865, a lipophilic quinazoline-based analogue of the antifolate thymidylate synthase inhibitor ICI 198583 with an undefined mechanism of action. Cytometry,  1998, 33(1), 56-66.
[http://dx.doi.org/10.1002/(SICI)1097-0320(19980901)33:1<56:AID-CYTO7>3.0.CO;2-9] [PMID: 9725559 ] 
[149] 
Dragovich, P.S.; Zhao, G.; Baumeister, T.; Bravo, B.; Giannetti, A.M.; Ho, Y.C.; Hua, R.; Li, G.; Liang, X.; Ma, X.; O’Brien, T.; Oh, A.; Skelton, N.J.; Wang, C.; Wang, W.; Wang, Y.; Xiao, Y.; Yuen, P.W.; Zak, M.; Zhao, Q.; Zheng, X. Fragment-based design of 3-aminopyridine-derived amides as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT). Bioorg. Med. Chem. Lett.,  2014, 24(3), 954-962.
[http://dx.doi.org/10.1016/j.bmcl.2013.12.062] [PMID: 24433859] 
Cite As
Current Medicinal Chemistry

Small Molecule Regulators Targeting NAD⁺Biosynthetic Enzymes

Abstract
