Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany.
Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
J Med Chem. 2022 Jul 28;65(14):9750-9788. doi: 10.1021/acs.jmedchem.2c00388. Epub 2022 Jul 18.
Selective manipulation of the epitranscriptome could be beneficial for the treatment of cancer and also broaden the understanding of epigenetic inheritance. Inhibitors of the tRNA methyltransferase DNMT2, the enzyme catalyzing the -adenosylmethionine-dependent methylation of cytidine 38 to 5-methylcytidine, were designed, synthesized, and analyzed for their enzyme-binding and -inhibiting properties. For rapid screening of potential DNMT2 binders, a microscale thermophoresis assay was established. Besides the natural inhibitors -adenosyl-l-homocysteine (SAH) and sinefungin (SFG), we identified new synthetic inhibitors based on the structure of -adenosyl-2,4-diaminobutyric acid (Dab). Structure-activity relationship studies revealed the amino acid side chain and a Y-shaped substitution pattern at the 4-position of Dab as crucial for DNMT2 inhibition. The most potent inhibitors are alkyne-substituted derivatives, exhibiting similar binding and inhibitory potencies as the natural compounds SAH and SFG. CaCo-2 assays revealed that poor membrane permeabilities of the acids and rapid hydrolysis of an ethylester prodrug might be the reasons for the insufficient activity in cellulo.
选择性地操纵表转录组可能有益于癌症的治疗，并拓宽对表观遗传遗传的理解。设计、合成并分析了 tRNA 甲基转移酶 DNMT2 的抑制剂，该酶催化 - 腺苷甲硫氨酸依赖性胞嘧啶 38 位至 5-甲基胞嘧啶的甲基化。为了快速筛选潜在的 DNMT2 结合物，建立了微尺度热泳测定法。除了天然抑制剂 - 腺苷-L-同型半胱氨酸（SAH）和 sinefungin（SFG）外，我们还基于 - 腺苷-2,4-二氨基丁酸（Dab）的结构确定了新的合成抑制剂。构效关系研究表明，Dab 的 4 位的氨基酸侧链和 Y 形取代模式对于 DNMT2 抑制至关重要。最有效的抑制剂是炔取代衍生物，其结合和抑制效力与天然化合物 SAH 和 SFG 相似。CaCo-2 测定表明，酸的膜通透性差和乙酯前药的快速水解可能是细胞内活性不足的原因。
