Identification of Potent and Selective Inhibitors of Fat Mass Obesity-Associated Protein Using a Fragment-Merging Approach
| Autor: | Yuri Takada, Yuki Kitao, Yoshie Fujiwara, Chika Yamamoto, Mitsuhiro Terao, Dan Ohtan Wang, Elghareeb E. Elboray, Yasunobu Yamashita, Yukihiro Itoh, Paolo Mellini, Rohini Roy, Yukari Takahashi, Makoto Oba, Masayuki Kotoku, Takao Yamaguchi, Satoshi Obika, Ritesh Singh, Muthuraj Prakash, Takayoshi Suzuki |
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| Rok vydání: | 2021 |
| Předmět: |
Adenosine
endocrine system diseases Alpha-Ketoglutarate-Dependent Dioxygenase FTO Down-Regulation Substrate Specificity chemistry.chemical_compound Downregulation and upregulation Cell Line Tumor Drug Discovery medicine Humans Acute monocytic leukemia Epigenetics Enzyme Inhibitors Gene Messenger RNA biology Chemistry nutritional and metabolic diseases RNA pathological conditions signs and symptoms medicine.disease Molecular biology Up-Regulation Drug Design biology.protein Molecular Medicine Demethylase DNA |
| Zdroj: | Journal of medicinal chemistry. 64(21) |
| ISSN: | 1520-4804 |
| Popis: | Fat mass obesity-associated protein (FTO) is a DNA/RNA demethylase involved in the epigenetic regulation of various genes and is considered a therapeutic target for obesity, cancer, and neurological disorders. Here, we aimed to design novel FTO-selective inhibitors by merging fragments of previously reported FTO inhibitors. Among the synthesized analogues, compound 11b, which merges key fragments of Hz (3) and MA (4), inhibited FTO selectively over alkylation repair homologue 5 (ALKBH5), another DNA/RNA demethylase. Treatment of acute monocytic leukemia NOMO-1 cells with a prodrug of 11b decreased the viability of acute monocytic leukemia cells, increased the level of the FTO substrate N6-methyladenosine in mRNA, and induced upregulation of MYC and downregulation of RARA, which are FTO target genes. Thus, Hz (3)/MA (4) hybrid analogues represent an entry into a new class of FTO-selective inhibitors. |
| Databáze: | OpenAIRE |
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