Targeting low-druggability bromodomains: fragment based screening and inhibitor design against the BAZ2B bromodomain

Fleur M. Ferguson, Oleg Fedorov, Apirat Chaikuad, Martin Philpott, Joao R. C. Muniz, Ildiko Felletar, Frank von Delft, Tom Heightman, Stefan Knapp, Chris Abell, Alessio Ciulli

    Research output: Contribution to journalArticlepeer-review

    72 Citations (Scopus)

    Abstract

    Bromodomains are epigenetic reader domains that have recently become popular targets. In contrast to BET bromodomains, which have proven druggable, bromodomains from other regions of the phylogenetic tree have shallower pockets. We describe successful targeting of the challenging BAZ2B bromodomain using biophysical fragment screening and structure-based optimization of high ligand-efficiency fragments into a novel series of low-micromolar inhibitors. Our results provide attractive leads for development of BAZ2B chemical probes and indicate the whole family may be tractable.
    Original languageEnglish
    Pages (from-to)10183-10187
    Number of pages5
    JournalJournal of Medicinal Chemistry
    Volume56
    Issue number24
    DOIs
    Publication statusPublished - Dec 2013

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