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

• Published in: ACS medicinal chemistry letters Vol. 7; no. 12; pp. 1102 - 1106
• Main Authors: Judge, Russell A, Zhu, Haizhong, Upadhyay, Anup K, Bodelle, Pierre M, Hutchins, Charles W, Torrent, Maricel, Marin, Violeta L, Yu, Wenyu, Vedadi, Masoud, Li, Fengling, Brown, Peter J, Pappano, William N, Sun, Chaohong, Petros, Andrew M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 08.12.2016; American Chemical Society (ACS)
• Subjects: 60 APPLIED LIFE SCIENCES; cancer; drug design; HMT; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Letter; SETD8; structure-based drug design; structure-based drug design; cancer; SETD8; drug design; HMT
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.6b00303

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.