Turning a Substrate Peptide into a Potent Inhibitor for the Histone Methyltransferase SETD8

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• 作者：Russell A. Judge ; Haizhong Zhu ; Anup K. Upadhyay ; Pierre M. Bodelle ; Charles W. Hutchins ; Maricel Torrent ; Violeta L. Marin ; Wenyu Yu ; Masoud Vedadi ; Fengling Li ; Peter J. Brown ; William N. Pappano ; Chaohong Sun ; Andrew M. Petros
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：December 8, 2016
• 年：2016
• 卷：7
• 期：12
• 页码：1102-1106
• 全文大小：347K
• ISSN：1948-5875

文摘

SETD8 is a histone H4–K20 methyltransferase that plays an essential role in the maintenance of genomic integrity during mitosis and in DNA damage repair, making it an intriguing target for cancer research. While some small molecule inhibitors for SETD8 have been reported, the structural binding modes for these inhibitors have not been revealed. Using the complex structure of the substrate peptide bound to SETD8 as a starting point, different natural and unnatural amino acid substitutions were tested, and a potent (K_i 50 nM, IC₅₀ 0.33 μM) and selective norleucine containing peptide inhibitor has been obtained.