1 research outputs found
Design of a Chemical Probe for the Bromodomain and Plant Homeodomain Finger-Containing (BRPF) Family of Proteins
The bromodomain and
plant homeodomain finger-containing (BRPF)
family are scaffolding proteins important for the recruitment of histone
acetyltransferases of the MYST family to chromatin. Here, we describe <b>NI-57</b> (<b>16</b>) as new pan-BRPF chemical probe of
the bromodomain (BRD) of the BRPFs. Inhibitor <b>16</b> preferentially
bound the BRD of BRPF1 and BRPF2 over BRPF3, whereas binding to BRD9
was weaker. Compound <b>16</b> has excellent selectivity over
nonclass IV BRD proteins. Target engagement of BRPF1B and BRPF2 with <b>16</b> was demonstrated in nanoBRET and FRAP assays. The binding
of <b>16</b> to BRPF1B was rationalized through an X-ray cocrystal
structure determination, which showed a flipped binding orientation
when compared to previous structures. We report studies that show <b>16</b> has functional activity in cellular assays by modulation
of the phenotype at low micromolar concentrations in both cancer and
inflammatory models. Pharmacokinetic data for <b>16</b> was
generated in mouse with single dose administration showing favorable
oral bioavailabilit