title: Docking and Linking of Fragments To Discover Jumonji Histone Demethylase Inhibitors.
abstract: Development of tool molecules that inhibit Jumonji demethylases allows for the investigation of cancer-associated transcription. While scaffolds such as 2,4-pyridinedicarboxylic acid (2,4-PDCA) are potent inhibitors, they exhibit limited selectivity. To discover new inhibitors for the KDM4 demethylases, enzymes overexpressed in several cancers, we docked a library of 600,000 fragments into the high-resolution structure of KDM4A. Among the most interesting chemotypes were the 5-aminosalicylates, which docked in two distinct but overlapping orientations. Docking poses informed the design of covalently linked fragment compounds, which were further derivatized. This combined approach improved affinity by ∼ 3 log-orders to yield compound 35 (Ki = 43 nM). Several hybrid inhibitors were selective for KDM4C over the related enzymes FIH, KDM2A, and KDM6B while lacking selectivity against the KDM3 and KDM5 subfamilies. Cocrystal structures corroborated the docking predictions. This study extends the use of structure-based docking from fragment discovery to fragment linking optimization, yielding novel KDM4 inhibitors.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Korczynska
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Le
authors.forename: Noah
authors.initials: N
authors.lastname: Younger
authors.forename: Elisabet
authors.initials: E
authors.lastname: Gregori-Puigjané
authors.affiliation: Structural Genomics Consortium, University of Oxford , Oxford OX3 7DQ, U.K.|Nuffield Department of Clinical Medicine, Target Discovery Institute (TDI), University of Oxford , Oxford OX3 7BN, U.K.
authors.forename: Anthony
authors.initials: A
authors.lastname: Tumber
authors.affiliation: Structural Genomics Consortium, University of Oxford , Oxford OX3 7DQ, U.K.
authors.forename: Tobias
authors.initials: T
authors.lastname: Krojer
authors.affiliation: Structural Genomics Consortium, University of Oxford , Oxford OX3 7DQ, U.K.
authors.forename: Srikannathasan
authors.initials: S
authors.lastname: Velupillai
authors.affiliation: Structural Genomics Consortium, University of Oxford , Oxford OX3 7DQ, U.K.
authors.forename: Carina
authors.initials: C
authors.lastname: Gileadi
authors.affiliation: Structural Genomics Consortium, University of Oxford , Oxford OX3 7DQ, U.K.
authors.forename: Radosław P
authors.initials: RP
authors.lastname: Nowak
authors.forename: Eriko
authors.initials: E
authors.lastname: Iwasa
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Pollock
authors.forename: Idelisse
authors.initials: I
authors.lastname: Ortiz Torres
authors.affiliation: Structural Genomics Consortium, University of Oxford , Oxford OX3 7DQ, U.K.|Botnar Research Center, University of Oxford , Oxford OX3 7LD, U.K.
authors.forename: Udo
authors.initials: U
authors.lastname: Oppermann
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
authors.forename: Danica Galonić
authors.initials: DG
authors.lastname: Fujimori
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D019804:Mesalamine / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D019804:Mesalamine; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human