Cancer Cell
Volume 35, Issue 4, 15 April 2019, Pages 677-691.e10
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Article
Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia

https://doi.org/10.1016/j.ccell.2019.03.006Get rights and content
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Highlights

  • Structure-guided design and optimization yield potent FTO inhibitors

  • mRNA m6A acts as the major effector of the inhibitor/FTO axis in AML cells

  • FTO inhibitor FB23-2 displays therapeutic effects in PDX AML models

  • Targeting epitranscriptomic RNA methylation holds potential to treat AML

Summary

FTO, an mRNA N6-methyladenosine (m6A) demethylase, was reported to promote leukemogenesis. Using structure-based rational design, we have developed two promising FTO inhibitors, namely FB23 and FB23-2, which directly bind to FTO and selectively inhibit FTO's m6A demethylase activity. Mimicking FTO depletion, FB23-2 dramatically suppresses proliferation and promotes the differentiation/apoptosis of human acute myeloid leukemia (AML) cell line cells and primary blast AML cells in vitro. Moreover, FB23-2 significantly inhibits the progression of human AML cell lines and primary cells in xeno-transplanted mice. Collectively, our data suggest that FTO is a druggable target and that targeting FTO by small-molecule inhibitors holds potential to treat AML.

Keywords

FTO inhibitor
RNA epitranscriptomics
acute myeloid leukemia
cancer therapy
target validation
structure-based design

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13

These authors contributed equally

14

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