The fat-mass and obesity-associated protein (FTO), a mRNA N6-methyladenosine (m6A) demethylase, is reported to promote leukemogenesis. FB23-2 is a potent and selective inhibitor of FTO, which binds directly to FTO and selectively inhibits FTO's m6A demethylase activity with an IC50 value of 2.6 μM. FB23-2 displayed significantly improved anti-proliferative activity on NB4 and MONOMAC6 cells with an IC50 of 0.8 – 1.5 μM and maintained inhibitory activity on FTO demethylation in vitro. FB23-2 substantially accelerated all-trans retinoic acid (ATRA)-induced myeloid differentiation in NB4 and MONOMAC6 cells in a dose-dependent manner. Furthermore, FB23-2 induced apoptosis and cell cycle arrest at G1 stage in AML cells. Collectively, these results suggest that FB23-2 exhibits FTO-dependent activity in AML cells. In a xeno-transplantation leukemic model, FB23-2 (2 mg/kg; intraperitoneally injected daily for 10 days) substantially delayed the onset of full-blown leukemic symptoms and significantly prolonged survival by almost doubling the median survival. Compared with the vehicle, FB23-2 treatment suppressed leukemia malignancy, including reduced splenomegaly and hepatomegaly, as well as the abundance of human AML cells in the recipient mice[1].
作用机制
FB23-2 unambiguously shows an intramolecular hydrogen bond between the amino hydrogen and the carbonyl of hydroxamic acid[1].
FB23-2 细胞实验
Cell Line
Concentration
Treated Time
Description
References
C666-1R cells
10 μmol
24-72 hours
FB23-2 significantly sensitized NPC cells to irradiation
Transl Oncol. 2023 Jan;27:101576.
Human umbilical vein endothelial cells (HUVECs)
10 μmol/L
48 hours
Nicotine dose-dependently upregulated FTO and NOX2 protein abundance, which were reversed by treatment with the FTO inhibitor FB23-2 or FTO knockdown using siRNAs.
Hypertension. 2024 Feb;81(2):240-251.
SiHa cells
1 µM
48 hours
FB23-2 treatment significantly down-regulated intracellular DIRAS1 mRNA levels, but significantly up-regulated DIRAS1 protein levels
Cancer Biol Ther. 2024 Dec 31;25(1):2306674.
C33A cells
1 µM
48 hours
FB23-2 treatment significantly down-regulated intracellular DIRAS1 mRNA levels, but significantly up-regulated DIRAS1 protein levels
Cancer Biol Ther. 2024 Dec 31;25(1):2306674.
HONE1R cells
10 μmol
24-72 hours
FB23-2 significantly sensitized NPC cells to irradiation
Transl Oncol. 2023 Jan;27:101576.
MV4-11 cells
5 μM
72 hours
Determination of m6A abundance in mRNA via dot blot assay
Cancer Cell. 2019 Apr 15;35(4):677-691.e10.
ML-2 cells
5 μM
72 hours
Determination of m6A abundance in mRNA via dot blot assay
Cancer Cell. 2019 Apr 15;35(4):677-691.e10.
U937 cells
5 μM
72 hours
Determination of m6A abundance in mRNA via dot blot assay
Cancer Cell. 2019 Apr 15;35(4):677-691.e10.
MA9.3RAS cells
5 μM
72 hours
Determination of m6A abundance in mRNA via dot blot assay
Cancer Cell. 2019 Apr 15;35(4):677-691.e10.
MA9.3ITD cells
5 μM
72 hours
Determination of m6A abundance in mRNA via dot blot assay
Cancer Cell. 2019 Apr 15;35(4):677-691.e10.
MONOMAC6 cells
20 μM
72 hours
Quantitation of the percentage of m6A/A and m6Am/A ratios in mRNA by LC-MS/MS
Cancer Cell. 2019 Apr 15;35(4):677-691.e10.
NB4 cells
20 μM
72 hours
Quantitation of the percentage of m6A/A and m6Am/A ratios in mRNA by LC-MS/MS
Cancer Cell. 2019 Apr 15;35(4):677-691.e10.
MONOMAC6 cells
10 μM
24 hours
Determination of cellular uptake of FB23-2 by LC-MS/MS quantitation
Cancer Cell. 2019 Apr 15;35(4):677-691.e10.
NB4 cells
10 μM
24 hours
Determination of cellular uptake of FB23-2 by LC-MS/MS quantitation
Cancer Cell. 2019 Apr 15;35(4):677-691.e10.
Human Umbilical Vein Endothelial Cells (HUVECs)
2 µM
48 hours
FB23-2 inhibits FTO's m6A demethylase activity, thereby suppressing high glucose-induced endothelial cell proliferation, migration, and tube formation.
EMBO Mol Med. 2024 Feb;16(2):294-318.
Human mesenchymal stem cells (hMSCs)
2.5 µM and 5 µM
7 days
To investigate the effect of FB23-2 on osteogenic differentiation of hMSCs, results showed that FB23-2 inhibited osteogenic differentiation of hMSCs.
Acta Pharmacol Sin. 2022 May;43(5):1311-1323.
FB23-2 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BALB/c mice
Not specified
Intraperitoneal injection (i.p.)
20 mg/kg
Daily for 14 days
Examination of the toxic effects of multi-doses of FB23-2 in BALB/c mice
Cancer Cell. 2019 Apr 15;35(4):677-691.e10.
Mice
Oxygen-induced retinopathy (OIR) mouse model
Intravenous injection
3 mg/kg
Daily injection for 5 days
NP-FB23-2 targets retinal neovascularization via intravenous injection, increases m6A modification levels in OIR retinas, and suppresses pathological neovascularization and endothelial tip cell formation.
EMBO Mol Med. 2024 Feb;16(2):294-318.
B-NDG mice
PDX model
Intraperitoneal injection
8 mg/kg/day
Continuously for 14 days
FB23-2 inhibited tumor growth and prolonged survival
Int J Biol Sci. 2022 Oct 3;18(15):5943-5962
C57BL/6J mice
Experimental autoimmune uveitis (EAU) model
Intravitreal injection
10 mmol/μL
Single injection, lasting 5 days
To investigate the effect of FB23-2 on the inflammatory response in EAU mice, results showed that FB23-2 significantly decreased retinal FTO expression and exacerbated ocular inflammation.
Genes Dis. 2022 Oct 4;10(5):2179-2193
BALB/c nude mice
HONE1R cell xenograft model
Intraperitoneal injection
2 mg/kg
Once every three days until the endpoint
FB23-2 significantly delayed the growth of HONE1R xenografts and enhanced radiation sensitivity
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