Artículos de revistas
Targeting low-druggability bromodomains: fragment based screening and inhibitor design against the BAZ2B bromodomain
Fecha
2013-12Registro en:
Journal of Medicinal Chemistry, Washington, DC : American Chemical Society - ACS, v. 56, n. 24, p. 10183-10187, Dec. 2013
0022-2623
10.1021/jm401582c
Autor
Ferguson, Fleur M.
Fedorov, Oleg
Chaikuad, Apirat
Philpott, Martin
Muniz, João Renato Carvalho
Felletar, Ildiko
Delft, Frank von
Heightman, Tom
Knapp, Stefan
Abell, Chris
Ciulli, Alessio
Institución
Resumen
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.