1,4,9-Triazaspiro[5.5]undecan-2-one Derivatives as Potent and Selective METTL3 Inhibitors
1,4,9-Triazaspiro[5.5]undecan-2-one Derivatives as Potent and Selective METTL3 Inhibitors
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DOI：
10.1021/acs.jmedchem.1c00773
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发表时间：
2021-08-25
影响因子：
7.3
通讯作者：
Caflisch, Amedeo
中科院分区：
文献类型：
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作者：
Dolbois, Aymeric;Bedi, Rajiv K.;Caflisch, Amedeo
N-6-甲基腺苷(m(6)A)是迄今报道的160种RNA修饰中最常见的一种。越来越多的证据表明，METTL3/METTL14蛋白复合体是m(6)A调节机制的一部分，在包括几种类型的癌症、2型糖尿病和病毒感染在内的各种疾病中起着关键作用。在这里，我们报告了一种基于蛋白质结晶学的药物化学优化，对一种METTL3 HIT化合物进行了药物化学优化，使效力提高了1400倍(在时间分辨Forster共振能量转移(TRRET)试验中，先导化合物22(UZH2)的IC50为5 NM)。该系列具有良好的ADME性能，因为在HIT优化过程中考虑了物理化学特性。UZH2显示了对细胞的靶向结合，并能够降低MOLM-13(急性髓系白血病)和PC-3(前列腺癌)细胞系中多聚腺化RNA的A/A水平。
N-6-methyladenosine (m(6)A) is the most frequent of the 160 RNA modifications reported so far. Accumulating evidence suggests that the METTL3/METTL14 protein complex, part of the m(6)A 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 Forster 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 m(6)A/A level of polyadenylated RNA in MOLM-13 (acute myeloid leukemia) and PC-3 (prostate cancer) cell lines.