m⁶A RNA methyltransferase (METTL3-14) catalyzes the methylation of adenosine in mRNA and plays important roles in mRNA functions, and it has been implicated in the progression of multiple cancers, including acute myeloid leukemia (AML). In this study, we describe the discovery of the first allosteric inhibitor of the METTL3-14 complex based on structure–activity relationship (SAR) and optimization studies of the hit compound, 4-[2-[5-chloro-1-(diphenylmethyl)-2-methyl-1H-indol-3-yl]-ethoxy]benzoic acid (CDIBA). Compound 43n was optimized throughout the modifications of 4 different regions of the structure, and it displayed potent enzyme inhibitory activity of the METTL3-14 complex (IC₅₀ = 2.81 μM) and an antiproliferative effect in the AML cell lines by suppressing the m⁶A level of mRNA. The inhibition mechanism and binding mode of 43n were based on the interaction of the reversible and noncompetitive inhibitory profile at the allosteric site along with selectivity for the METTL3-14 complex relative to each subunit enzyme or truncated complex enzyme.

中文翻译：

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发现取代的吲哚衍生物作为 m6A-RNA 甲基转移酶 METTL3-14 复合物的变构抑制剂

m ⁶ RNA 甲基转移酶 (METTL3-14) 催化 mRNA 中腺苷的甲基化并在 mRNA 功能中发挥重要作用，它与多种癌症的进展有关，包括急性髓性白血病 (AML)。在这项研究中，我们描述了基于构效关系 (SAR) 的 METTL3-14 复合物的第一个变构抑制剂的发现和命中化合物 4-[2-[5-chloro-1-(diphenylmethyl) 的优化研究。 )-2-甲基-1H-吲哚-3-基]-乙氧基]苯甲酸 (CDIBA)。化合物43n在结构的 4 个不同区域的修饰中进行了优化，并显示出 METTL3-14 复合物的有效酶抑制活性（IC ₅₀ = 2.81 μM)，并通过抑制 m ⁶ A mRNA 水平在 AML 细胞系中发挥抗增殖作用。43n的抑制机制和结合模式基于变构位点的可逆和非竞争性抑制谱的相互作用以及 METTL3-14 复合物相对于每个亚基酶​​或截短复合酶的选择性。