6AKW

Crystal structure of RNA dioxygenase bound with an inhibitor

Summary for 6AKW

• Entry DOI: 10.2210/pdb6akw/pdb
• Descriptor: Alpha-ketoglutarate-dependent dioxygenase FTO, 2-OXOGLUTARIC ACID, 2-[[2,6-bis(chloranyl)-4-(3,5-dimethyl-1,2-oxazol-4-yl)phenyl]amino]benzoic acid, ... (4 entities in total)
• Functional Keywords: rna demethylase, inhibitor, oxidation, rna binding protein, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 57048.99

Authors

Yang, C.-G.,Huang, Y.,Gan, J. (deposition date: 2018-09-04, release date: 2019-05-29, Last modification date: 2023-11-22)

Primary citation

Huang, Y.,Su, R.,Sheng, Y.,Dong, L.,Dong, Z.,Xu, H.,Ni, T.,Zhang, Z.S.,Zhang, T.,Li, C.,Han, L.,Zhu, Z.,Lian, F.,Wei, J.,Deng, Q.,Wang, Y.,Wunderlich, M.,Gao, Z.,Pan, G.,Zhong, D.,Zhou, H.,Zhang, N.,Gan, J.,Jiang, H.,Mulloy, J.C.,Qian, Z.,Chen, J.,Yang, C.G.
Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia.
Cancer Cell, 35:677-691.e10, 2019

PubMed Abstract: FTO, an mRNA N-methyladenosine (mA) 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 mA 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.

PubMed: 30991027
DOI: 10.1016/j.ccell.2019.03.006

Experimental method

X-RAY DIFFRACTION (2.2 Å)