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m6A-RNA Demethylase FTO Inhibitors Impair Self-Renewal in Glioblastoma Stem Cells
ACS Chemical Biology ( IF 4 ) Pub Date : 2021-01-07 , DOI: 10.1021/acschembio.0c00841
Sarah Huff 1 , Shashi Kant Tiwari 1 , Gwendolyn M Gonzalez 2 , Yinsheng Wang 2 , Tariq M Rana 1, 3
Affiliation  

N6-methyladenosine (m6A) has emerged as the most abundant mRNA modification that regulates gene expression in many physiological processes. m6A modification in RNA controls cellular proliferation and pluripotency and has been implicated in the progression of multiple disease states, including cancer. RNA m6A methylation is controlled by a multiprotein “writer” complex including the enzymatic factor methyltransferase-like protein 3 (METTL3) that regulates methylation and two “eraser” proteins, RNA demethylase ALKBH5 (ALKBH5) and fat mass- and obesity-associated protein (FTO), that demethylate m6A in transcripts. FTO can also demethylate N6,2′-O-dimethyladenosine (m6Am), which is found adjacent to the m7G cap structure in mRNA. FTO has recently gained interest as a potential cancer target, and small molecule FTO inhibitors such as meclofenamic acid have been shown to prevent tumor progression in both acute myeloid leukemia and glioblastoma in vivo models. However, current FTO inhibitors are unsuitable for clinical applications due to either poor target selectivity or poor pharmacokinetics. In this work, we describe the structure-based design, synthesis, and biochemical evaluation of a new class of FTO inhibitors. Rational design of 20 small molecules with low micromolar IC50’s and specificity toward FTO over ALKBH5 identified two competitive inhibitors FTO-02 and FTO-04. Importantly, FTO-04 prevented neurosphere formation in patient-derived glioblastoma stem cells (GSCs) without inhibiting the growth of healthy neural stem cell-derived neurospheres. Finally, FTO-04 increased m6A and m6Am levels in GSCs consistent with FTO inhibition. These results support FTO-04 as a potential new lead for treatment of glioblastoma.

中文翻译:

m6A-RNA 去甲基化酶 FTO 抑制剂损害胶质母细胞瘤干细胞的自我更新

N 6 -甲基腺苷 (m 6 A) 已成为最丰富的 mRNA 修饰,可在许多生理过程中调节基因表达。m 6 RNA 中的修饰控制细胞增殖和多能性,并且与多种疾病状态的进展有关,包括癌症。RNA m 6 A 甲基化由多蛋白“写入器”复合物控制,包括调节甲基化的酶因子甲基转移酶样蛋白 3 (METTL3) 和两种“擦除”蛋白、RNA 去甲基化酶 ALKBH5 (ALKBH5) 和脂肪量和肥胖相关蛋白质 (FTO),使转录物中的m 6 A去甲基化。FTO 还可以使N 6 ,2'- O去甲基化-二甲基腺苷 (m 6 A m ),它与mRNA 中的 m 7 G 帽结构相邻。FTO 最近作为潜在的癌症靶点引起了人们的兴趣,并且小分子 FTO 抑制剂如甲氯芬那酸已被证明可以在体内模型中阻止急性髓性白血病和胶质母细胞瘤的肿瘤进展。然而,由于靶标选择性差或药代动力学差,目前的 FTO 抑制剂不适合临床应用。在这项工作中,我们描述了一类新型 FTO 抑制剂的基于结构的设计、合成和生化评估。20个小分子的合理设计,低微摩尔IC 50对 FTO 超过 ALKBH5 的特异性和特异性确定了两种竞争性抑制剂 FTO-02 和 FTO-04。重要的是,FTO-04 阻止了患者来源的胶质母细胞瘤干细胞 (GSC) 中神经球的形成,而不会抑制健康的神经干细胞来源的神经球的生长。最后,FTO-04 增加了 GSC 中的m 6 A 和 m 6 A m水平,与 FTO 抑制一致。这些结果支持 FTO-04 作为治疗胶质母细胞瘤的潜在新线索。
更新日期:2021-02-19
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