title: Design and Synthesis of Simplified Largazole Analogues as Isoform-Selective Human Lysine Deacetylase Inhibitors.
abstract: Selective inhibition of KDAC isoforms while maintaining potency remains a challenge. Using the largazole macrocyclic depsipeptide structure as a starting point for developing new KDACIs with increased selectivity, a combination of four different simplified largazole analogue (SLA) scaffolds with diverse zinc-binding groups (for a total of 60 compounds) were designed, synthesized, and evaluated against class I KDACs 1, 3, and 8, and class II KDAC6. Experimental evidence as well as molecular docking poses converged to establish the cyclic tetrapeptides (CTPs) as the primary determinant of both potency and selectivity by influencing the correct alignment of the zinc-binding group in the KDAC active site, providing a further basis for developing new KDACIs of higher isoform selectivity and potency.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine , 700 South Euclid Avenue, St. Louis, Missouri 63110, United States.
authors.forename: Damodara N
authors.initials: DN
authors.lastname: Reddy
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine , 700 South Euclid Avenue, St. Louis, Missouri 63110, United States.
authors.forename: Flavio
authors.initials: F
authors.lastname: Ballante
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine , 700 South Euclid Avenue, St. Louis, Missouri 63110, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: Chuang
authors.affiliation: Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma , P. le A. Moro 5, 00185 Roma, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: Pirolli
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma , P. le A. Moro 5, 00185 Roma, Italy.
authors.forename: Biagina
authors.initials: B
authors.lastname: Marrocco
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine , 700 South Euclid Avenue, St. Louis, Missouri 63110, United States.
authors.forename: Garland R
authors.initials: GR
authors.lastname: Marshall
mesh_terms: D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D020033:Protein Isoforms; D013844:Thiazoles; C527895:largazole; D006655:Histone Deacetylases