Small-Molecule Inhibitors of SETD8 with Cellular Activity

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• 作者：Gil Blum ; Glorymar Ib谩帽ez ; Xiangjun Rao ; David Shum ; Constantin Radu ; Hakim Djaballah ; Judd C. Rice ; Minkui Luo
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：November 21, 2014
• 年：2014
• 卷：9
• 期：11
• 页码：2471-2478
• 全文大小：408K
• ISSN：1554-8937

文摘

SETD8/SET8/Pr-SET7/KMT5A is the sole protein lysine methyltransferase (PKMT) known to monomethylate lysine 20 of histone H4 in vivo. SETD8鈥檚 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鈥? (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鈥? against SETD8, together with their distinct structures and mechanisms for SETD8 inhibition, argues for the collective application of these compounds as SETD8 inhibitors.