jm7b00611_si_002.csv (3.15 kB)
Design of a Chemical Probe for the Bromodomain and Plant Homeodomain Finger-Containing (BRPF) Family of Proteins
dataset
posted on 2017-07-17, 00:00 authored by Niall Igoe, Elliott D. Bayle, Cynthia Tallant, Oleg Fedorov, Julia C. Meier, Pavel Savitsky, Catherine Rogers, Yannick Morias, Sarah Scholze, Helen Boyd, Danen Cunoosamy, David M. Andrews, Anne Cheasty, Paul E. Brennan, Susanne Müller, Stefan Knapp, Paul V. FishThe 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 NI-57 (16) as new pan-BRPF chemical probe of
the bromodomain (BRD) of the BRPFs. Inhibitor 16 preferentially
bound the BRD of BRPF1 and BRPF2 over BRPF3, whereas binding to BRD9
was weaker. Compound 16 has excellent selectivity over
nonclass IV BRD proteins. Target engagement of BRPF1B and BRPF2 with 16 was demonstrated in nanoBRET and FRAP assays. The binding
of 16 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 16 has functional activity in cellular assays by modulation
of the phenotype at low micromolar concentrations in both cancer and
inflammatory models. Pharmacokinetic data for 16 was
generated in mouse with single dose administration showing favorable
oral bioavailability
