GNE-235: A Lead Compound Selective for the Second Bromodomain of PBRM1

Bromodomains
are acetyl-lysine binding modules that are found in
different classes of chromatin-interacting proteins. Among these are
large chromatin remodeling complexes such as BAF and PBAF (variants
of human SWI/SNF). Previous work has identified chemical probes targeting
a subset of the bromodomains present in the BAF and PBAF complexes.
Selective inhibitors of the individual bromodomains have proven challenging
to discover, as the domains are highly similar. Here, elaboration
of an aminopyridazine scaffold used previously to develop probes for
the bromodomains of SMARCA2, SMARCA4, and the fifth bromodomain of
PBRM1 yielded compounds with both potency and unusual selectivity
for the second bromodomain of PBRM1. One of these, GNE-235, and its
enantiomer control GNE-234 are suggested for initial cellular investigations
of the function of the second bromodomain of PBRM1.