Igoe, Niall Bayle, Elliott D. Tallant, Cynthia Fedorov, Oleg Meier, Julia C. Savitsky, Pavel Rogers, Catherine Morias, Yannick Scholze, Sarah Boyd, Helen Cunoosamy, Danen Andrews, David M. Cheasty, Anne Brennan, Paul E. Mùˆller, Susanne Knapp, Stefan Fish, Paul V. 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 bioavailability BRPF 2;FRAP;MYST;nonclass IV BRD proteins;NI;plant homeodomain finger-containing;BRPF 1B;Plant Homeodomain Finger-Containing;X-ray cocrystal structure determination;pan-BRPF chemical probe 2017-07-17
    https://acs.figshare.com/articles/journal_contribution/Design_of_a_Chemical_Probe_for_the_Bromodomain_and_Plant_Homeodomain_Finger-Containing_BRPF_Family_of_Proteins/5296417
10.1021/acs.jmedchem.7b00611.s001