Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2.
Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2.
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DOI：
10.1021/acs.jmedchem.5b01890
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发表时间：
2016-05-26
影响因子：
7.3
通讯作者：
Stresemann C
中科院分区：
文献类型：
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作者：
Eggert E;Hillig RC;Koehr S;Stöckigt D;Weiske J;Barak N;Mowat J;Brumby T;Christ CD;Ter Laak A;Lang T;Fernandez-Montalvan AE;Badock V;Weinmann H;Hartung IV;Barsyte-Lovejoy D;Szewczyk M;Kennedy S;Li F;Vedadi M;Brown PJ;Santhakumar V;Arrowsmith CH;Stellfeld T;Stresemann C
蛋白质赖氨酸甲基转移酶最近已成为一个新的目标类别的发展抑制剂，调节基因转录或信号通路。SET和MYND结构域包含蛋白2（SMYD2）是一种催化性SET结构域包含甲基转移酶，据报道可将组蛋白和非组蛋白蛋白上的赖氨酸残基单甲基化。虽然一些研究已经发现SMYD2在通过蛋白质甲基化促进癌症中的重要作用，但SMYD2的生物学还远未完全理解。利用高效和选择性的化学探针进行靶点验证已经成为一种概念，它规避了敲除实验的可能限制，特别是可以改善对具有复杂基础生物学的药物靶点的探索。在这里，我们报告了一种有效的，选择性的，细胞活性的，底物竞争性的SMYD2抑制剂的开发，这是第一个报告的抑制剂适合在啮齿动物体内靶点验证研究。
Protein lysine methyltransferases have recently emerged as a new target class for the development of inhibitors that modulate gene transcription or signaling pathways. SET and MYND domain containing protein 2 (SMYD2) is a catalytic SET domain containing methyltransferase reported to monomethylate lysine residues on histone and nonhistone proteins. Although several studies have uncovered an important role of SMYD2 in promoting cancer by protein methylation, the biology of SMYD2 is far from being fully understood. Utilization of highly potent and selective chemical probes for target validation has emerged as a concept which circumvents possible limitations of knockdown experiments and, in particular, could result in an improved exploration of drug targets with a complex underlying biology. Here, we report the development of a potent, selective, and cell-active, substrate-competitive inhibitor of SMYD2, which is the first reported inhibitor suitable for in vivo target validation studies in rodents.