Turning a Substrate Peptide into a Potent Inhibitor for the Histone Methyltransferase SETD8 [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 540.86 Chemistry and allied sciences
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2016
• Mô tả vật lý: Size: p. 1102-1106 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260751
• Chủ đề: 1. 37 inorganic, organic, physical, and analytical chemistry; 2. 60 applied life sciences; 3. Cancer; 4. Drug design; 5. Hmt; 6. Setd8; 7. Structure-based drug design

Tóm tắt

 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 (Ki 50 nM, IC<
 sub>
 50<
 /sub>
  0.33 ?M) and selective norleucine containing peptide inhibitor has been obtained.