title: Turning a Substrate Peptide into a Potent Inhibitor for the Histone Methyltransferase SETD8.
abstract: 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 (Ki50 nM, IC500.33 μM) and selective norleucine containing peptide inhibitor has been obtained.
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Russell A
authors.initials: RA
authors.lastname: Judge
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Haizhong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Anup K
authors.initials: AK
authors.lastname: Upadhyay
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Pierre M
authors.initials: PM
authors.lastname: Bodelle
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Hutchins
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Maricel
authors.initials: M
authors.lastname: Torrent
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Violeta L
authors.initials: VL
authors.lastname: Marin
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Yu
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Fengling
authors.initials: F
authors.lastname: Li
authors.affiliation: Structural Genomics Consortium, University of Toronto , 101 College Street, Toronto, ON M5G 1L7, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: William N
authors.initials: WN
authors.lastname: Pappano
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Chaohong
authors.initials: C
authors.lastname: Sun
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Petros
keywords: HMT; SETD8; cancer; drug design; structure-based drug design