Structure-Activity Relationships of 2-(Arylthio)benzoic Acid FTO Inhibitors

IF 2.3 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY
Chao Yan, Qian Zhang, Pan Xiao, Xinyun Xie, Ming Li, Yuanlai Qiu, Liufa Wen, Xiaomin Song, Ze Dong, Cai-Guang Yang
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引用次数: 0

Abstract

The biological role of the fat mass and obesity-associated protein (FTO) in the initiation and progress of acute myeloid leukemia (AML) has been elucidated, and several representative FTO inhibitors can markedly suppress the proliferation of AML cells. We previously developed FTO inhibitors including FB23. In this study, we adopted bioisosteric replacement of the intramolecular hydrogen bond in FB23 with a sulfur-oxygen interaction to generate a series of 2-(arylthio)benzoic acid FTO inhibitors and established their structure-activity relationships. Compound 8c was the most potent 2-(arylthio)benzoic acid FTO inhibitor with an IC50 value of 0.3±0.1 μM, which was comparable with that of FB23 in vitro. To enhance the antiproliferative effects in AML cell lines, we applied a prodrug strategy and prepared some esters. 7l, the methyl ester of 8l, exerted a superior inhibitory effect on a panel of AML cancer cell lines. Additionally, 7l treatment notably increased global m6A abundance in AML cells. Collectively, our data suggest that 2-(arylthio)benzoic acid may be a new lead compound for inhibition of FTO, and the prodrug analog exhibit potential in the treatment of AML.

Abstract Image

Abstract Image

2-(芳硫基)苯甲酸 FTO 抑制剂的结构-活性关系
脂肪量和肥胖相关蛋白(FTO)在急性髓性白血病(AML)的发病和进展中的生物学作用已被阐明,几种具有代表性的 FTO 抑制剂可明显抑制 AML 细胞的增殖。我们之前开发了包括 FB23 在内的 FTO 抑制剂。在本研究中,我们采用生物异构法将 FB23 分子内氢键置换成硫氧相互作用,生成了一系列 2-(芳硫基)苯甲酸 FTO 抑制剂,并建立了它们的结构-活性关系。化合物 8c 是最有效的 2-(芳硫基)苯甲酸 FTO 抑制剂,其 IC50 值为 0.3±0.1 μM,与 FB23 在体外的 IC50 值相当。为了增强对 AML 细胞株的抗增殖作用,我们采用了原药策略,制备了一些酯类化合物。7l 是 8l 的甲酯,对一组急性髓细胞癌细胞株有很好的抑制作用。此外,7l 还能显著增加 AML 细胞中 m6A 的丰度。总之,我们的数据表明,2-(芳硫基)苯甲酸可能是抑制 FTO 的一种新的先导化合物,其原药类似物在治疗急性髓细胞性白血病方面具有潜力。
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来源期刊
Israel Journal of Chemistry
Israel Journal of Chemistry 化学-化学综合
CiteScore
6.20
自引率
0.00%
发文量
62
审稿时长
6-12 weeks
期刊介绍: The fledgling State of Israel began to publish its scientific activity in 1951 under the general heading of Bulletin of the Research Council of Israel, which quickly split into sections to accommodate various fields in the growing academic community. In 1963, the Bulletin ceased publication and independent journals were born, with Section A becoming the new Israel Journal of Chemistry. The Israel Journal of Chemistry is the official journal of the Israel Chemical Society. Effective from Volume 50 (2010) it is published by Wiley-VCH. The Israel Journal of Chemistry is an international and peer-reviewed publication forum for Special Issues on timely research topics in all fields of chemistry: from biochemistry through organic and inorganic chemistry to polymer, physical and theoretical chemistry, including all interdisciplinary topics. Each topical issue is edited by one or several Guest Editors and primarily contains invited Review articles. Communications and Full Papers may be published occasionally, if they fit with the quality standards of the journal. The publication language is English and the journal is published twelve times a year.
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