Bromodomains
(BD) are readers of lysine acetylation marks present
in numerous proteins associated with chromatin. Here we describe a
dual inhibitor of the bromodomain and PHD finger (BRPF) family member
BRPF2 and the TATA box binding protein-associated factors TAF1 and
TAF1L. These proteins are found in large chromatin complexes and play
important roles in transcription regulation. The substituted benzoisoquinolinedione
series was identified by high-throughput screening, and subsequent
structure–activity relationship optimization allowed generation
of low nanomolar BRPF2 BD inhibitors with strong selectivity against
BRPF1 and BRPF3 BDs. In addition, a strong inhibition of TAF1/TAF1L
BD2 was measured for most derivatives. The best compound of the series
was BAY-299, which is a very potent, dual inhibitor with an IC50 of 67 nM for BRPF2 BD, 8 nM for TAF1 BD2, and 106 nM for
TAF1L BD2. Importantly, no activity was measured for BRD4 BDs. Furthermore,
cellular activity was evidenced using a BRPF2– or TAF1–histone
H3.3 or H4 interaction assay.