GNE-064: A Potent, Selective, and Orally Bioavailable Chemical Probe for the Bromodomains of SMARCA2 and SMARCA4 and the Fifth Bromodomain of PBRM1

Bromodomains are acetyllysine recognition domains present
in a
variety of human proteins. Bromodomains also bind small molecules
that compete with acetyllysine, and therefore bromodomains have been
targets for drug discovery efforts. Highly potent and selective ligands
with good cellular permeability have been proposed as chemical probes
for use in exploring the functions of many of the bromodomain proteins.
We report here the discovery of a class of such inhibitors targeting
the family VIII bromodomains of SMARCA2 (BRM) and SMARCA4 (BRG1),
and PBRM1 (polybromo-1) bromodomain 5. We propose one example from
this series, GNE-064, as a chemical probe for the bromodomains SMARCA2,
SMARCA4, and PBRM1(5) with the potential for in vivo use.