N⁶-methyladenosine (m⁶A) is the most frequent of the 160 RNA modifications reported so far. Accumulating evidence suggests that the METTL3/METTL14 protein complex, part of the m⁶A regulation machinery, is a key player in a variety of diseases including several types of cancer, type 2 diabetes, and viral infections. Here we report on a protein crystallography-based medicinal chemistry optimization of a METTL3 hit compound that has resulted in a 1400-fold potency improvement (IC₅₀ of 5 nM for the lead compound 22 (UZH2) in a time-resolved Förster resonance energy transfer (TR-FRET) assay). The series has favorable ADME properties as physicochemical characteristics were taken into account during hit optimization. UZH2 shows target engagement in cells and is able to reduce the m⁶A/A level of polyadenylated RNA in MOLM-13 (acute myeloid leukemia) and PC-3 (prostate cancer) cell lines.

中文翻译：

---

1,4,9-Triazaspiro[5.5]undecan-2-one 衍生物作为有效和选择性 METTL3 抑制剂

N ⁶ -甲基腺苷 (m ⁶ A) 是迄今为止报道的 160 种 RNA 修饰中最常见的。越来越多的证据表明，METTL3/METTL14 蛋白复合物是 m ⁶ A 调节机制的一部分，是多种疾病的关键参与者，包括多种类型的癌症、2 型糖尿病和病毒感染。在这里，我们报告了基于蛋白质晶体学的 METTL3 命中化合物的药物化学优化，该优化导致效力提高了 1400 倍（先导化合物22 ( UZH2) 的IC ₅₀为 5 nM) 在时间分辨 Förster 共振能量转移 (TR-FRET) 测定中）。该系列具有良好的 ADME 特性，因为在命中优化过程中考虑了物理化学特性。UZH2在细胞中显示出靶标参与，并且能够降低MOLM-13（急性髓性白血病）和 PC-3（前列腺癌）细胞系中多腺苷酸化 RNA的 m ⁶ A/A 水平。