title: An efficient high-throughput screening method for MYST family acetyltransferases, a new class of epigenetic drug targets.
abstract: Epigenetic aberrations are increasingly regarded as key factors in cancer progression. Recently, deregulation of histone acetyltransferases (HATs) has been linked to several types of cancer. Monocytic leukemia zinc finger protein (MOZ) is a member of the MYST family of HATs, which regulate gene expression in cell proliferation and differentiation. Deregulation of these processes through constitutively active MOZ fusion proteins gives rise to the formation of leukemic stem cells, rendering MOZ an excellent target for treating myeloid leukemia. The authors implemented a hit discovery campaign to identify small-molecule inhibitors of MOZ-HAT activity. They developed a robust, homogeneous assay measuring the acetylation of synthetic histone peptides. In a primary screening campaign testing 243 000 lead-like compounds, they identified inhibitors from several chemical classes. Secondary assays were used to eliminate assay-interfering compounds and prioritize confirmed hits. This study establishes a new high-throughput assay for HAT activity and could provide the foundation for the development of a new class of drugs for the treatment of leukemias.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. falk@wehi.edu.au
authors.forename: Hendrik
authors.initials: H
authors.lastname: Falk
authors.forename: Theresa
authors.initials: T
authors.lastname: Connor
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Loft
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Alcindor
authors.forename: George
authors.initials: G
authors.lastname: Nikolakopoulos
authors.forename: Regina N
authors.initials: RN
authors.lastname: Surjadi
authors.forename: John D
authors.initials: JD
authors.lastname: Bentley
authors.forename: Meghan K
authors.initials: MK
authors.lastname: Hattarki
authors.forename: Olan
authors.initials: O
authors.lastname: Dolezal
authors.forename: James M
authors.initials: JM
authors.lastname: Murphy
authors.forename: Brendon J
authors.initials: BJ
authors.lastname: Monahan
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Peat
authors.forename: Tim
authors.initials: T
authors.lastname: Thomas
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Baell
authors.forename: John P
authors.initials: JP
authors.lastname: Parisot
authors.forename: Ian P
authors.initials: IP
authors.lastname: Street
mesh_terms: D004789:Enzyme Activation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects*; D057166:High-Throughput Screening Assays / Q000379:methods*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015203:Reproducibility of Results; D054852:Small Molecule Libraries
chemical_list: D054852:Small Molecule Libraries; D051548:Histone Acetyltransferases; C108712:KAT6A protein, human