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
AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
Structural Genomics Consortium, University of Toronto , 101 College Street, Toronto, ON M5G 1L7, Canada.
ACS Med Chem Lett. 2016 Oct 11;7(12):1102-1106. doi: 10.1021/acsmedchemlett.6b00303. eCollection 2016 Dec 8.
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 ( 50 nM, IC 0.33 μM) and selective norleucine containing peptide inhibitor has been obtained.
SETD8是一种组蛋白H4-K20甲基转移酶，在有丝分裂期间基因组完整性的维持以及DNA损伤修复中发挥着重要作用，这使其成为癌症研究中一个引人关注的靶点。虽然已经报道了一些针对SETD8的小分子抑制剂，但这些抑制剂的结构结合模式尚未揭示。以与SETD8结合的底物肽的复合物结构为起点，测试了不同的天然和非天然氨基酸取代，获得了一种强效（50 nM，IC 0.33 μM）且具有选择性的含正亮氨酸的肽抑制剂。
