title: Structure-activity relationship studies of SETD8 inhibitors.
abstract: SETD8 (also known as SET8, PR-SET7, or KMT5A (lysine methyltransferase 5A)) is the only known lysine methyltransferase that catalyzes monomethylation of histone H4 lysine 20 (H4K20). In addition to H4K20, SETD8 monomethylates non-histone substrates such as the tumor suppressor p53 and proliferating cell nuclear antigen (PCNA). Because of its role in regulating diverse biological processes, SETD8 has been pursued as a potential therapeutic target. We recently reported the first substrate-competitive SETD8 inhibitor, UNC0379 (1), which is selective for SETD8 over 15 other methyltransferases. We characterized this inhibitor in a battery of biochemical and biophysical assays. Here we describe our comprehensive structure-activity relationship (SAR) studies of this chemical series. In addition to 2- and 4-substituents, we extensively explored 6- and 7-substituents of the quinazoline scaffold. These SAR studies led to the discovery of several new compounds, which displayed similar potencies as compound1, and interesting SAR trends.
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, United States.
authors.forename: Anqi
authors.initials: A
authors.lastname: Ma
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, United States.
authors.forename: Kyle V
authors.initials: KV
authors.lastname: Butler
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, United States ; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, United States ; Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin