Small-molecule inhibitors of SETD8 with cellular activity.
Small-molecule inhibitors of SETD8 with cellular activity.
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DOI：
10.1021/cb500515r
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发表时间：
2014-11-21
影响因子：
4
通讯作者：
Luo, Minkui
中科院分区：
文献类型：
--
作者：
Blum, Gil;Ibanez, Glorymar;Rao, Xiangjun;Shum, David;Radu, Constantin;Djaballah, Hakim;Rice, Judd C.;Luo, Minkui
SETD8/SET8/Pr-SET7/KMT5A是体内唯一已知的能单甲基化组蛋白H4赖氨酸20的蛋白赖氨酸甲基转移酶（PKMT）。SETD8的甲基转移酶活性涉及许多基本的细胞过程，包括DNA复制，DNA损伤反应，转录调节和细胞周期调节。开发具有细胞活性的SETD8抑制剂是通过方便的药理学扰动阐明SETD8的多种作用的关键一步。从先前的高通量筛选（HTS）中，SPS8I1-3 （NSC663284， BVT948和ryuvidine）被验证为有效的SETD8抑制剂。这些化合物含有不同的结构基序，并通过不同的模式抑制SETD8。更重要的是，这些化合物通过抑制SETD8的H4K20me1标记和重现rnai介导的SETD8敲低所观察到的特征S/G2/ m期细胞周期缺陷来显示细胞活性。SPS8I1-3抗SETD8的共性，以及它们独特的结构和抑制SETD8的机制，证明了这些化合物作为SETD8抑制剂的共同应用。
SETD8/SET8/Pr-SET7/KMT5A is the sole protein lysine methyltransferase (PKMT) known to monomethylate lysine 20 of histone H4 in vivo. SETD8’s methyltransferase activity has been implicated in many essential cellular processes including DNA replication, DNA damage response, transcription modulation, and cell cycle regulation. Developing SETD8 inhibitors with cellular activity is a key step toward elucidating the diverse roles of SETD8 via convenient pharmacological perturbation. From the hits of a prior high throughput screen (HTS), SPS8I1–3 (NSC663284, BVT948, and ryuvidine) were validated as potent SETD8 inhibitors. These compounds contain different structural motifs and inhibit SETD8 via distinct modes. More importantly, these compounds show cellular activity by suppressing the H4K20me1 mark of SETD8 and recapitulate characteristic S/G2/M-phase cell cycle defects as observed for RNAi-mediated SETD8 knockdown. The commonality of SPS8I1–3 against SETD8, together with their distinct structures and mechanisms for SETD8 inhibition, argues for the collective application of these compounds as SETD8 inhibitors.
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DOI：
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发表时间：
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影响因子：
3.5
作者：
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DOI：
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发表时间：
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影响因子：
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