FTO抑制剂抗肺癌机制研究

As the most abundant internal mRNA modification, m6A plays a key role in the regulations of gene expressions and impacts various biological processes such as mRNA metabolisms, stem cell self-renewal and circadian clock controlling etc. FTO, the first identified mRNA N6-methyladenosine (m6A) demethylase, was reported to promote leukemogenesis. Our previous studies had demonstrated that small-molecule inhibitors targeting oncogenic FTO represent a novel strategy for leukemia therapy. Although emerging evidences prove that deregulation of FTO demethylation leads to the progression of solid tumors, small-molecule inhibitors targeting the FTO demethylase for solid tumor therapy and mode of action haven’t been claimed. The newly inhibitor (named with FB23-2) developed by the applicant have a broad anti- proliferation activity on several lung cancer cell lines. In this funding program, chemical intervention and genetic approaches will be fully combined to screen the sensitive cell lines and reveal the principles behind the critical genes and signaling pathways regulated by FTO in variety of lung cancer types. The application of chemical biology will adequately disclose the action modes of inhibitors, which helps demostrate the feasibility of small-molecule inhibitors targeting FTO for solid tumor supression and promote the studies of epitranscriptome regulation and drug discovery.

6-甲基腺嘌呤（m6A）是真核mRNA上最广泛的修饰，是调控基因表达的关键，影响了如RNA代谢、干性维持、生物节律等多种生物学过程。FTO是首个发现的m6A去甲基化酶，过表达促进白血病生成。申请人前期工作确证了FTO小分子抑制剂抗白血病的可行性。虽然文献报道FTO去甲基化功能紊乱介导实体瘤的发生，靶向性的FTO抑制剂是否可以抗实体瘤及其作用机制未有报道。申请人发展的抑制剂对若干株肺癌细胞系具有抑制细胞增殖的活性，本项目中拟利用FTO抑制剂（FB23-2）为小分子工具，筛选对FTO抑制剂敏感的肺癌细胞系，充分运用化学干预的方法，结合基因编辑技术，分析FTO在不同类型肺癌中调控的靶基因和通路，揭示FTO在肺癌发生中的机制。研究中注重化学生物学技术上的运用，以充分表征小分子调控的作用模式。本课题研究结果将确证小分子靶向FTO抗实体瘤的可行性，推动RNA表观遗传基础生物学以及靶向性新药发现研究。

以6-甲基腺嘌呤（m6A）修饰为核心的RNA表观转录是基础生物学和药物发现的活跃前沿，m6A及其修饰酶功能的紊乱与肿瘤等疾病的发生密不可分。去甲基化酶FTO在急性髓系白血病AML和肺癌等肿瘤中起到关键促进作用，因此利用小分子化学干预FTO去甲基化酶有助于加深对FTO调控特定肿瘤发生分子机制的理解，推动靶向FTO抗肿瘤的化学生物学研究。本项目聚焦化学干预 RNA去甲基化酶 FTO 的表型及其作用机制研究，充分利用多种结构新颖、活性显著、选择性高的FTO抑制剂作为化学探针，主要取得两方面进展，包括1）发展FTO新型金属配合物类抑制剂，并开展抗肺癌细胞增殖的作用机制研究；2）开展三环苯甲酸类FTO抑制剂的构效关系研究，并进行抗AML的药效评价。本项目研究成果进一步确证小分子靶向FTO抗肿瘤的可行性，提供了骨架新颖、药理性质良好的先导化合物，推动了RNA表观转录的生物学及药物新靶标发现研究。该项目共发表论文2篇，申请专利4项。