Discovery of a Potent Class I Protein Arginine Methyltransferase Fragment Inhibitor
Discovery of a Potent Class I Protein Arginine Methyltransferase Fragment Inhibitor
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DOI：
10.1021/acs.jmedchem.5b01772
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发表时间：
2016-02-11
影响因子：
7.3
通讯作者：
Schapira, Matthieu
中科院分区：
文献类型：
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作者：
de Freitas, Renato Ferreira;Eram, Mohammad S.;Schapira, Matthieu
蛋白质甲基转移酶（PMT）是肿瘤学和其他疾病领域的一个有前途的目标类别。它们由SET结构域甲基转移酶和结构上不相关的罗斯曼折叠酶组成，包括蛋白质精氨酸甲基转移酶（PRMT）。在没有一个明确的药物化学工具包集中在PMT，目前大多数抑制剂的筛选大型和多样化的图书馆的leadlike分子。到目前为止，没有成功的片段为基础的方法，针对这一目标类别的报告。在这里，通过解构有效的PRMT抑制剂，我们发现，占据底物精氨酸结合位点的化学部分可以作为有效的片段抑制剂。针对PRMT 6筛选片段文库产生了大量命中，包括300 nM抑制剂（配体效率为0.56），其降低了细胞中的全局组蛋白3精氨酸2甲基化，并且可以作为开发PRMT化学探针的弹头。
Protein methyltransferases (PMTs) are a promising target class in oncology and other disease areas. They are composed of SET domain methyltransferases and structurally unrelated Rossman-fold enzymes that include protein arginine methyltransferases (PRMTs). In the absence of a well-defined medicinal chemistry tool-kit focused on PMTs, most current inhibitors were identified by screening large and diverse libraries of leadlike molecules. So far, no successful fragment-based approach was reported against this target class. Here, by deconstructing potent PRMT inhibitors, we find that chemical moieties occupying the substrate arginine-binding site can act as efficient fragment inhibitors. Screening a fragment library against PRMT6 produced numerous hits, including a 300 nM inhibitor (ligand efficiency of 0.56) that decreased global histone 3 arginine 2 methylation in cells, and can serve as a warhead for the development of PRMT chemical probes.