FK866 (APO866)

FK866 (APO866) is a potent and selective inhibitor of nicotinamide phosphoribosyltransferase (NAMPT) (K_i=0.3nM). FK866 blocks the conversion of nicotinamide to nicotinamide mononucleotide (NMN), thereby depleting intracellular NAD⁺ and ATP. FK866 triggers caspase-independent tumor cell death by inducing mitochondrial membrane depolarization and autophagy. FK866 can be used in studies related to tumor metabolism, hematological malignancies, and NAD⁺ homeostasis regulation^[1-4].

In vitro, FK866 (0-40nM) was applied to human hepatocellular carcinoma MHCC97-H cells for 24-72h. FK866 inhibited NAMPT expression and reduced intracellular NAD⁺ and ATP levels. FK866 suppressed epithelial-mesenchymal transition, and inhibited cell viability, migration, and invasion ability^[5]. FK866 (5nM) was applied to human pancreatic ductal adenocarcinoma KP4 cells, PANC-1 cells, and mouse 4T1 and MC38 cells for 24h. FK866 inhibited compensatory glycolysis and induced oxidative stress and cell death. FK866 (5nM) combined with metformin activated p53 pathway and unfolded protein response-related gene expression, enhancing anti-tumor effects^[6].

In vivo, FK866 (10mg/kg; three times) was intraperitoneally injected into C57BL/6 mice with acute liver failure at 24h, 12h, and 0.5h before modeling. FK866 alleviated hepatotoxicity, enhanced autophagic activity, inhibited JNK activation, reduced serum alanine aminotransferase and aspartate aminotransferase levels, and decreased hepatocyte necrosis and inflammatory cell infiltration^[7]. FK866 (1-10mg/kg) was intraperitoneally injected into C57BL/6J mice with bleomycin (3mg/kg; intratracheal instillation)-induced pulmonary fibrosis, once daily from one day before modeling to 14 days after modeling, for a total of 16 days. FK866 alleviated bleomycin-induced lung inflammation and collagen deposition, reduced NAMPT levels and release of cytokines such as TNF-α, IL-6, and TGF-β1 in bronchoalveolar lavage fluid. FK866 decreased M2 macrophage infiltration in the lungs, ameliorated body weight loss, and improved survival rate^[8].

References:
[1] Xie H, Lei Y, Mao Y, et al. FK866 inhibits colorectal cancer metastasis by reducing NAD⁺ levels in cancer-associated fibroblasts. Genes Genomics. 2022 Dec;44(12):1531-1541.
[2] Pant K, Richard S, Peixoto E, et al. The NAMPT Inhibitor FK866 in Combination with Cisplatin Reduces Cholangiocarcinoma Cells Growth. Cells. 2023 Feb 28;12(5):775.
[3] Tan Z, Chen L, Ren Y, et al. Neuroprotective effects of FK866 against traumatic brain injury: Involvement of p38/ERK pathway. Ann Clin Transl Neurol. 2020 May;7(5):742-756.
[4] Ok CY, Park S, Jang HO, et al. FK866 Protects Human Dental Pulp Cells against Oxidative Stress-Induced Cellular Senescence. Antioxidants (Basel). 2021 Feb 10;10(2):271.
[5] Zhang B, Shi D, Zhang X, et al. FK866 inhibits the epithelial-mesenchymal transition of hepatocarcinoma MHCC97-H cells. Oncol Lett. 2018 Nov;16(5):7231-7238.
[6] Parisotto M, Vuong-Robillard N, Kalegari P, et al. The NAMPT Inhibitor FK866 Increases Metformin Sensitivity in Pancreatic Cancer Cells. Cancers. 2022 Nov;14(22):5597.
[7] Guo E, Li R, Yang J, et al. FK866 attenuates acute hepatic failure through c-jun-N-terminal kinase(JNK)-dependent autophagy. Sci Rep. 2017 May 19;7:2206.
[8] Chen Y, Wang T, Liang F, et al. Nicotinamide phosphoribosyltransferase prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice. Theranostics. 2024 Apr;14(7):2794-2815.