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

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.

SUBMITTER: Ferguson FM

PROVIDER: S-EPMC3905694 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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

Ferguson Fleur M FM Fedorov Oleg O Chaikuad Apirat A Philpott Martin M Muniz Joao R C JR Felletar Ildiko I von Delft Frank F Heightman Tom T Knapp Stefan S Abell Chris C Ciulli Alessio A

Journal of medicinal chemistry 20131213 24

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 deve ...[more]

PMID: 24304323

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