Discovery of a selective, substrate-competitive inhibitor of the lysine methyltransferase SETD8.
Discovery of a selective, substrate-competitive inhibitor of the lysine methyltransferase SETD8.
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DOI：
10.1021/jm500871s
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发表时间：
2014-08-14
影响因子：
7.3
通讯作者：
Jin J
中科院分区：
文献类型：
--
作者：
Ma A;Yu W;Li F;Bleich RM;Herold JM;Butler KV;Norris JL;Korboukh V;Tripathy A;Janzen WP;Arrowsmith CH;Frye SV;Vedadi M;Brown PJ;Jin J
赖氨酸甲基转移酶SETD8是唯一已知的催化组蛋白H4赖氨酸20（H4K20）单甲基化的甲基转移酶。H4K20的单甲基化涉及调节多种生物学过程，包括DNA损伤反应。除了H4K20之外，SETD8还使包括增殖细胞核抗原（PCNA）在内的非组蛋白底物单甲基化，并通过解除PCNA表达的调节来促进癌发生。然而，SETD 8的选择性抑制剂很少。迄今为止，唯一已知的SETD 8选择性抑制剂是nahuoic acid A，一种海洋天然产物，它与辅因子竞争。在这里，我们报告了第一个SETD 8底物竞争性抑制剂UNC0379的发现（1）。这种小分子抑制剂在多种生化测定中具有活性。通过ITC（等温滴定量热法）和SPR（表面等离子体共振）研究证实了其对SETD8的亲和力。重要的是，化合物1对SETD 8的选择性超过15种其他甲基转移酶。我们还描述了这一系列的构效关系（SAR）。
The lysine methyltransferase SETD8 is the only known methyltransferase that catalyzes monomethylation of histone H4 lysine 20 (H4K20). Monomethylation of H4K20 has been implicated in regulating diverse biological processes including the DNA damage response. In addition to H4K20, SETD8 monomethylates non-histone substrates including proliferating cell nuclear antigen (PCNA) and promotes carcinogenesis by deregulating PCNA expression. However, selective inhibitors of SETD8 are scarce. The only known selective inhibitor of SETD8 to date is nahuoic acid A, a marine natural product, which is competitive with the cofactor. Here, we report the discovery of the first substrate-competitive inhibitor of SETD8, UNC0379 (1). This small-molecule inhibitor is active in multiple biochemical assays. Its affinity to SETD8 was confirmed by ITC (isothermal titration calorimetry) and SPR (surface plasmon resonance) studies. Importantly, compound 1 is selective for SETD8 over 15 other methyltransferases. We also describe structure–activity relationships (SAR) of this series.
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通讯作者：
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