Small-Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer.,ChemMedChem

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Small-Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-03-23 , DOI: 10.1002/cmdc.202000011
Rajiv K Bedi ₁ , Danzhi Huang ₁ , Stefanie A Eberle _{1,

2} , Lars Wiedmer ₁ , Pawel Śledź ₁ , Amedeo Caflisch ₁

Affiliation

The RNA methylase METTL3 catalyzes the transfer of a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to the N6 atom of adenine. We have screened a library of 4000 analogues and derivatives of the adenosine moiety of SAM by high-throughput docking into METTL3. Two series of adenine derivatives were identified in silico, and the binding mode of six of the predicted inhibitors was validated by protein crystallography. Two compounds, one for each series, show good ligand efficiency. We propose a route for their further development into potent and selective inhibitors of METTL3.

中文翻译：

METTL3的小分子抑制剂，人类主要的转录组作者。

RNA甲基化酶METTL3催化甲基从辅因子S-腺苷-L-甲硫氨酸（SAM）到腺嘌呤的N6原子的转移。我们已经通过高通量对接入METTL3筛选了SAM的4000个类似物和腺苷部分衍生物的文库。在计算机上鉴定出两个系列的腺嘌呤衍生物，并通过蛋白质晶体学验证了六种预测抑制剂的结合模式。两种化合物（每个系列一个）显示出良好的配体效率。我们提出了将其进一步开发为METTL3的有效和选择性抑制剂的途径。

更新日期：2020-03-23

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