A4381-50mg | FK866 (APO866) [658084-64-1] Clinisciences

Background

FK866 is an inhibitor of nicotinamide phosphoribosyltransferase (NMPRTase) with IC50 values ranging between 0.09 nM and 27.2 nM [1].

NAD plays a vital role in numerous biochemical and biologic processes. Targeting NAD synthesis is thought to be a selective manner to kill cancer cells since cancer cells have a higher rate of NAD turnover compared with normal cells. In the in vitro MTT assay using a panel of 41 human hematologic cancer

cell lines, most cancer cells are sensitive to low concentrations of FK866. Among these cancer cells, AML cells are most sensitive. FK866 is shown selective to human hematologic malignant cells and the normal human HPCs are resistant to FK866 treatment. It is found that FK866 induces cell death in a caspase-independent pathway but in a dose-dependent manner to induce mitochondrial membrane depolarization. Additionally, FK866 induces cell autophagy dependenting on de novo protein synthesis. FK866 also reduces ATP levels in ML-2 cells due to the inhibition of NAD synthesis. The antitumor efficacy of FK866 is also shown in the in vivo models. FK866 significantly prevents tumor growth both in mice xenografted subcutaneously with AML-M4 and Namalwa cells. Furthermore, FK866 clears tumor cells to below detectable levels and results in 80% survival for a long-term [1].

References:
[1] 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.

Product Citation

1. Qingrui Zhuan， Jun Li, et al. "Nampt affects mitochondrial function in aged oocytes by mediating the downstream effector FoxO3a." J Cell Physiol. 2022 Jan;237(1):647-659. PMID:34318928
2. Juvita D Iljas, Zhe Wei, et al. "Sirt1 sustains female fertility by slowing age‐related decline in oocyte quality required for post‐fertilization embryo development." Aging Cell. 2020;00:e13204. PMID:32729989
3. Zhe Wei, Jessica Greaney, et al. "Nampt-mediated spindle sizing secures a post-anaphase increase in spindle speed required for extreme asymmetry." Nature Communications volume 11, Article number: 3393 (2020);07 July 2020. PMID:32636388
4. Huang Y, Peng Y, et al. "Nicotinamide Phosphoribosyl Transferase Controls NLRP3 Inflammasome Activity Through MAPK and NF-κB Signaling in Nucleus Pulposus Cells, as Suppressed by Melatonin." Inflammation. 2020;10.1007/s10753-019-01166-z. PMID:31900828
5. Shi KL, Qian JY, et al. "Atorvastatin antagonizes the visfatin-induced expression of inflammatory mediators via the upregulation of NF-κB activation in HCAECs." Oncol Lett. 2016 Aug;12(2):1438-1444. PMID:27446449

Chemical Properties

Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	391.51
Cas No.	658084-64-1
Formula	C24H29N3O2
Solubility	insoluble in H2O; ≥19.6 mg/mL in DMSO; ≥49.6 mg/mL in EtOH
Chemical Name	(E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-pyridin-3-ylprop-2-enamide
SDF	Download SDF
Canonical SMILES	C1CN(CCC1CCCCNC(=O)C=CC2=CN=CC=C2)C(=O)C3=CC=CC=C3
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment [1]:
Cell lines	41 hematologic malignant cell lines
Preparation method	The solubility of this compound in DMSO is limited. General tips for obtaining a higher concentration: Please warm the tube at 37°C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20°C for several months.
Reaction Conditions	0-10 nM; 72 or 96 hrs
Applications	In various hematologic cancer cells, APO866 (0-10 nM) dose-dependently induced depletion of intracellular NAD and ATP contents and cell death.
Animal experiment [1]:
Animal models	C.B.-17 SCID mice xenograft models of human AML, lymphoblastic lymphoma and leukemia
Dosage form	20 mg/kg; i.p.; twice daily for 4 days, repeated weekly 3 times
Applications	In C.B.-17 SCID mice xenograft models of human AML, lymphoblastic lymphoma and leukemia, APO866 prevented and abrogated tumor growth.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1] Nahimana A, Attinger A, Aubry D, Greaney P, Ireson C, Thougaard AV, Tj?rnelund 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.

Biological Activity

Description	FK866 is a highly specific non-competitive inhibitor of nicotinamide phosphoribosyltransferase (NAMPT) with Ki value of 0.4 nM.
Targets	NAMPT
IC50	0.4 nM (Ki)