9knh
Structural complex of FTO bound with Dac590
Structural highlights
DiseaseFTO_HUMAN Defects in FTO are the cause of growth retardation developmental delay coarse facies and early death (GDFD) [MIM:612938. A severe polymalformation syndrome characterized by postnatal growth retardation, microcephaly, severe psychomotor delay, functional brain deficits and characteristic facial dysmorphism. In some patients, structural brain malformations, cardiac defects, genital anomalies, and cleft palate are observed. Early death occurs by the age of 3 years.[1] FunctionFTO_HUMAN Dioxygenase that repairs alkylated DNA and RNA by oxidative demethylation. Has highest activity towards single-stranded RNA containing 3-methyluracil, followed by single-stranded DNA containing 3-methylthymine. Has low demethylase activity towards single-stranded DNA containing 1-methyladenine or 3-methylcytosine. Has no activity towards 1-methylguanine. Has no detectable activity towards double-stranded DNA. Requires molecular oxygen, alpha-ketoglutarate and iron. Contributes to the regulation of the global metabolic rate, energy expenditure and energy homeostasis. Contributes to the regulation of body size and body fat accumulation.[2] [3] Publication Abstract from PubMedN(6)-Methyladenosine (m(6)A), the most prevalent mRNA modification, undergoes dynamic regulation mediated by the demethylase fat mass and obesity-associated protein (FTO), which is aberrantly overexpressed in acute myeloid leukemia (AML) and drives leukemogenesis. Based on the structure-guided optimization of our previously reported FTO inhibitor Dac85 and fluorescein, we developed Dac590, a tricyclic benzoic acid derivative with potent FTO inhibitory activity and improved pharmacokinetic properties. Dac590 exerts a robust antiproliferative effect on AML cells by suppressing oncogenic FTO signaling. Oral administration of Dac590 significantly inhibited xenograft tumor growth and prolonged survival in AML mouse models with no observed toxicity. Notably, Dac590 synergized with decitabine to enhance DNA hypomethylation and further improve the survival rates. Our study identifies Dac590 as a potent orally bioavailable FTO inhibitor and demonstrates a combinatorial strategy through dual epigenetic modulations for enhanced AML therapy. Development of Orally Bioavailable FTO Inhibitors with Potent Antileukemia Efficacy.,Yang T, Dong Z, Du R, Wang Y, Liu L, Xue Y, Zhang X, Liao Y, Gan J, Yu X, Huang Y, Yang CG J Med Chem. 2025 Jul 10;68(13):13714-13727. doi: 10.1021/acs.jmedchem.5c00566. , Epub 2025 Jun 28. PMID:40579742[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
