Open AccessTurning a Substrate Peptide into a Potent Inhibitor for the Histone Methyltransferase SETD8
Author(s) -
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
Publication year - 2016
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.6b00303
Subject(s) - histone methyltransferase , histone , peptide , histone h4 , chemistry , methyltransferase , biochemistry , dna , methylation
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, IC 50 0.33 μM) and selective norleucine containing peptide inhibitor has been obtained.