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APO-866

APO-866 (FK866) is a small molecule with potential antineoplastic and antiangiogenic activities. NMPRTase inhibitor APO866 binds to and inhibits nicotinamide phosphoribosyltransferase (NMPRTase), inhibiting the biosynthesis of nicotinamide adenine dinucleotide (NAD+) from niacinamide (vitamin B3), which may deplete energy reserves in metabolically active tumor cells and induce tumor cell apoptosis. In addition, this agent may inhibit tumor cell prioduction of vascular endothelial growth factor (VEGF), resulting in the inhibition of tumor angiogenesis. The coenzyme NAD+ plays an essential role in cellular redox reactions, including the redox reaction linking the citric acid cycle and oxidative phosphorylation. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:   TopoTarget USA, Inc.

Anticancer activity of APO866 on C6 glioblastoma cells. APO866 is a potent inhibitor of NAMPT against C6 glioblastoma.  APO866 inhibited the growth of C6 glioblastoma cells with IC(50) in nano-molar range. APO866 depleted intracellular NAD, caused marked inhibition of ERK activation and induced G2/M cell-cycle arrest. The effects by APO866 were abrogated by nicotinamide mononucleotide (NMN), the direct product of NAMPT. Administration of U0126, an ERK1/2 inhibitor, inhibited cell growth but displayed no synergistic effect with APO866. Taken together, the results indicated that APO866 is a potent growth inhibitor against glioblastoma through targeting NAMPT. (source: Eur J Pharmacol. 2012 Jan 15;674(2-3):163-70).

Anticancer activity of FK866 on gastric cancer  in combination with fluorouracil. APO866 (FK866) was found to suppress gastric cancer cell migration and anchorage-independent growth, respectively. These inhibitory effects of FK866 were accompanied by significantly decreased expression of VEGF, MMP2, MMP9 and NF-κB. As determined by MTT assay and flow cytometry, FK866 also increased the chemo-sensitivity of gastric cancer cells to fluorouracil by greater inhibition of cell proliferation and the induction of apoptosis. Our findings indicate that Nampt may be a new therapeutic target for gastric (source: Oncol Rep. 2011 Nov;26(5):1251-7.).

Antitumoral activities of APO866 (FK866) in neuroblastoma cells. It was confirmed that FK866 alone in neuroblastoma cells induced autophagy, and its effects were potentiated by chloroquine and antagonized by 3-methyladenine or by down-regulating autophagy-related protein 7. Autophagy, in this model, seemed to be crucial for FK866-induced cell death. On the other hand, a striking potentiation of the effects of cisplatin and etoposide was given by cotreatment of cells with ineffective concentrations of FK866 (1 nM). The effect of etoposide on DNA damage is potentiated by FK866 treatment, whereas the effect of FK866 on cytosolic NAD depletion is potentiated by etoposide. Even more strikingly, cotreatment with etoposide/cisplatin and FK866 unmasks an effect on mitochondrial NAD depletion. (source: J Pharmacol Exp Ther. 2011 Sep;338(3):829-40.).

 1: Zhang LY, Liu LY, Qie LL, Ling KN, Xu LH, Wang F, Fang SH, Lu YB, Hu H, Wei EQ, Zhang WP. Anti-proliferation effect of APO866 on C6 glioblastoma cells by inhibiting nicotinamide phosphoribosyltransferase. Eur J Pharmacol. 2012 Jan 15;674(2-3):163-70. Epub 2011 Nov 19. PubMed PMID: 22119381.

2: Evans L, Williams AS, Hayes AJ, Jones SA, Nowell M. Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre-B cell colony-enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866-mediated therapy in human fibroblasts and murine collagen-induced arthritis. Arthritis Rheum. 2011 Jul;63(7):1866-77. doi: 10.1002/art.30338. PubMed PMID: 21400478.

3: Zoppoli G, Cea M, Soncini D, Fruscione F, Rudner J, Moran E, Caffa I, Bedognetti D, Motta G, Ghio R, Ferrando F, Ballestrero A, Parodi S, Belka C, Patrone F, Bruzzone S, Nencioni A. Potent synergistic interaction between the Nampt inhibitor APO866 and the apoptosis activator TRAIL in human leukemia cells. Exp Hematol. 2010 Nov;38(11):979-88. Epub 2010 Aug 7. PubMed PMID: 20696207.

4: Yang HJ, Yen MC, Lin CC, Lin CM, Chen YL, Weng TY, Huang TT, Wu CL, Lai MD. A combination of the metabolic enzyme inhibitor APO866 and the immune adjuvant L-1-methyl tryptophan induces additive antitumor activity. Exp Biol Med (Maywood). 2010 Jul;235(7):869-76. PubMed PMID: 20558841.

5: Olesen UH, Thougaard AV, Jensen PB, Sehested M. A preclinical study on the rescue of normal tissue by nicotinic acid in high-dose treatment with APO866, a specific nicotinamide phosphoribosyltransferase inhibitor. Mol Cancer Ther. 2010 Jun;9(6):1609-17. Epub 2010 Jun 1. PubMed PMID: 20515945.

6: Cea M, Zoppoli G, Bruzzone S, Fruscione F, Moran E, Garuti A, Rocco I, Cirmena G, Casciaro S, Olcese F, Pierri I, Cagnetta A, Ferrando F, Ghio R, Gobbi M, Ballestrero A, Patrone F, Nencioni A. APO866 activity in hematologic malignancies: a preclinical in vitro study. Blood. 2009 Jun 4;113(23):6035-7; author reply 6037-8. PubMed PMID: 19498032.

7: Nahimana A, Attinger A, Aubry D, Greaney P, Ireson C, Thougaard AV, Tjørnelund J, Dawson KM, Dupuis M, Duchosal MA. The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies. Blood. 2009 Apr 2;113(14):3276-86. Epub 2009 Feb 5. PubMed PMID: 19196867.

1: Bi TQ, Che XM, Liao XH, Zhang DJ, Long HL, Li HJ, Zhao W. Overexpression of Nampt in gastric cancer and chemopotentiating effects of the Nampt inhibitor FK866 in combination with fluorouracil. Oncol Rep. 2011 Nov;26(5):1251-7. doi: 10.3892/or.2011.1378. Epub 2011 Jul 4. PubMed PMID: 21743967.

2: Travelli C, Drago V, Maldi E, Kaludercic N, Galli U, Boldorini R, Di Lisa F, Tron GC, Canonico PL, Genazzani AA. Reciprocal potentiation of the antitumoral activities of FK866, an inhibitor of nicotinamide phosphoribosyltransferase, and etoposide or cisplatin in neuroblastoma cells. J Pharmacol Exp Ther. 2011 Sep;338(3):829-40. Epub 2011 Jun 17. PubMed PMID: 21685314.

3: Kang GB, Bae MH, Kim MK, Im I, Kim YC, Eom SH. Crystal structure of Rattus norvegicus Visfatin/PBEF/Nampt in complex with an FK866-based inhibitor. Mol Cells. 2009 Jun 30;27(6):667-71. Epub 2009 Jun 12. PubMed PMID: 19533035.

4: Galli U, Ercolano E, Carraro L, Blasi Roman CR, Sorba G, Canonico PL, Genazzani AA, Tron GC, Billington RA. Synthesis and biological evaluation of isosteric analogues of FK866, an inhibitor of NAD salvage. ChemMedChem. 2008 May;3(5):771-9. PubMed PMID: 18247435.

5: Billington RA, Genazzani AA, Travelli C, Condorelli F. NAD depletion by FK866 induces autophagy. Autophagy. 2008 Apr;4(3):385-7. Epub 2008 Jan 23. PubMed PMID: 18227641.

6: Holen K, Saltz LB, Hollywood E, Burk K, Hanauske AR. The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor. Invest New Drugs. 2008 Feb;26(1):45-51. Epub 2007 Oct 9. PubMed PMID: 17924057.

7: Pogrebniak A, Schemainda I, Azzam K, Pelka-Fleischer R, Nüssler V, Hasmann M. Chemopotentiating effects of a novel NAD biosynthesis inhibitor, FK866, in combination with antineoplastic agents. Eur J Med Res. 2006 Aug 30;11(8):313-21. PubMed PMID: 17052966.

8: Drevs J, Löser R, Rattel B, Esser N. Antiangiogenic potency of FK866/K22.175, a new inhibitor of intracellular NAD biosynthesis, in murine renal cell carcinoma. Anticancer Res. 2003 Nov-Dec;23(6C):4853-8. PubMed PMID: 14981935.

9: 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 Nov 1;63(21):7436-42. PubMed PMID: 14612543.

Patents related to this agent:

1. Sassone-Corsi, Paolo; Nakahata, Yasukazu. Compositions and methods related to SIRT1 function in circadian gene regulation. PCT Int. Appl. (2010), 216pp. CODEN: PIXXD2 WO 2010011331 A2 20100128 CAN 152:161049 AN 2010:110428

2. Dang, Chi V.; Le, Quy Hoa Thi; Dinavahi, Ramani. Methods for treating neoplasia by inhibiting lactate dehydrogenase and/or nicotinamide phosphoribosyltransferase. PCT Int. Appl. (2010), 126pp. CODEN: PIXXD2 WO 2010002465 A2 20100107 CAN 152:136704 AN 2010:20864

3. Leo, Oberdan; Van Gool, Frederic; Galli, Mara; Flamand, Veronique; Loi, Patrizia; De Smedt, Thibaut. Use of NAD formation inhibitors for the treatment of ischemia-reperfusion injury. PCT Int. Appl. (2009), 81pp. CODEN: PIXXD2 WO 2009109610 A1 20090911 CAN 151:350827 AN 2009:1107823

4. Leo, Oberdan; Van Gool, Frederic; Galli, Mara; Flamand, Veronique; Loi, Patrizia; De Smedt, Thibaut. Use of NAD formation inhibitors for the treatment of ischemia-reperfusion injury. Eur. Pat. Appl. (2009), 66pp. CODEN: EPXXDW EP 2098231 A1 20090909 CAN 151:305200 AN 2009:1102075

5. Roulston, Anne; Beauparlant, Pierre. Compositions and methods for effecting NAD+ levels using a nicotinamide phosphoribosyl transferase inhibitor. U.S. Pat. Appl. Publ. (2009), 52 pp., Cont.-in-part of U.S. Ser. No. 237,755. CODEN: USXXCO US 2009215823 A1 20090827 CAN 151:260671 AN 2009:1048775

6. Roulston, Anne; Beauparlant, Pierre. Compositions and methods for effecting NAD+ levels using pyridyl cyanoguanidine compound nicotinamide phosphoribosyl transferase inhibitors, and use in cancer treatment. PCT Int. Appl. (2009), 149pp. CODEN: PIXXD2 WO 2009072004 A2 20090611 CAN 151:49316 AN 2009:703127

7. Oberdan, Leo; De Smedt, Thibaut; Van Gool, Frederic; Galli, Mara. New method for the treatment of inflammatory diseases. PCT Int. Appl. (2008), 22pp. CODEN: PIXXD2 WO 2008026018 A1 20080306 CAN 148:299893 AN 2008:289582

8. Oberdan, Leo; De Smedt, Thibaut; Van Gool, Frederic; Galli, Mara. New method for the treatment of inflammatory diseases. PCT Int. Appl. (2008), 108pp. CODEN: PIXXD2 WO 2008025857 A2 20080306 CAN 148:323112 AN 2008:289581

9. Tong, Liang; Tao, Xiao; Khan, Javed A. Crystal structure of human and murine visfatin and ligand complexes, and drug design applications. U.S. Pat. Appl. Publ. (2008), 36pp. CODEN: USXXCO US 2008020413 A1 20080124 CAN 148:185810 AN 2008:95259

10. Yasuhiro, Tetsuya; Kitajima, Takashi; Wakamatsu, Daisuke; Kamoshima, Wataru. Agent for reduction of bleeding in cerebrovascular disorder. PCT Int. Appl. (2006), 44pp. CODEN: PIXXD2 WO 2006137510 A1 20061228 CAN 146:93553 AN 2006:1357083