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].
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