title: Development of novel Asf1-H3/H4 inhibitors.
abstract: The histone chaperone anti-silencing function 1 (Asf1) has emerged as a promising target for therapeutic intervention for multiple cancers (Cell2006, 127, 458). Asf1 is involved in the packaging of the eukaryotic genome into chromatin, which is essential for normal growth, development, and differentiation, as this regulates all nuclear processes that use DNA as a substrate. Starting from a collection of HTS leads, we identified a series of N-acyl hydrazones as novel inhibitors of the Asf-histone H3/H4 interaction. These compounds represent the first example of inhibitors capable of disrupting the Asf1-H3/H4 complex.
authors.affiliation: Colorado Center for Drug Discovery, Colorado State University, Department of Chemistry, Fort Collins, CO 80523-1872, USA. Electronic address: Greg.Miknis@Colostate.edu.
authors.forename: Greg F
authors.initials: GF
authors.lastname: Miknis
authors.affiliation: Colorado Center for Drug Discovery, Colorado State University, Department of Chemistry, Fort Collins, CO 80523-1872, USA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Stevens
authors.affiliation: Department of Pharmacology and the Program in Structural Biology and Biochemistry, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Luke E
authors.initials: LE
authors.lastname: Smith
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610-3633, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Ostrov
authors.affiliation: Department of Pharmacology and the Program in Structural Biology and Biochemistry, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Mair E A
authors.initials: ME
authors.lastname: Churchill
mesh_terms: D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D006657:Histones / Q000037:antagonists & inhibitors*; D006801:Humans; D018832:Molecular Chaperones
chemical_list: C491641:ASF1A protein, human; D018797:Cell Cycle Proteins; D006657:Histones; D018832:Molecular Chaperones
keywords: Asf1; Drug discovery; H3/H4; Histone chaperone; Hydrazone