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Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia.
- Source :
-
Cancer Cell . Apr2019, Vol. 35 Issue 4, p677-677. 1p. - Publication Year :
- 2019
-
Abstract
- 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. • 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 Huang et al. use structure-based rational design to develop FB23-2, an inhibitor of the mRNA m6A demethylase FTO. FB23-2 suppresses proliferation and promotes the differentiation of acute myeloid leukemia (AML) cells and prolongs survival of patient-derived AML mouse models. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15356108
- Volume :
- 35
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- Cancer Cell
- Publication Type :
- Academic Journal
- Accession number :
- 136072404
- Full Text :
- https://doi.org/10.1016/j.ccell.2019.03.006