Igoe, N; Bayle, ED; Tallant, C; Fedorov, O; Meier, JC; Savitsky, P; Rogers, C; ... Fish, PV; + view all Igoe, N; Bayle, ED; Tallant, C; Fedorov, O; Meier, JC; Savitsky, P; Rogers, C; Morias, Y; Scholze, S; Boyd, H; Cunoosamy, D; Andrews, DM; Cheasty, A; Brennan, PE; Müller, S; Knapp, S; Fish, PV; - view fewer (2017) Design of a chemical probe for the Bromodomain and Plant Homeodomain Finger-containing (BRPF) family of proteins. Journal of Medicinal Chemistry , 60 (16) pp. 6998-7011. 10.1021/acs.jmedchem.7b00611.

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Abstract

The bromodomain and PHD 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 BRD1 over BRPF3, whereas binding to BRD9 was weaker. 16 has excellent selectivity over non-class IV BRD proteins. Target engagement of BRPF1B and BRD1 with 16 was demonstrated in nanoBRET and FRAP assays. The binding of 16 to BRPF1B was rationalized through an X-ray co-crystal 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 μmolar concentrations in both cancer and inflammatory models. Pharmacokinetic data for 16 was generated in mouse with single dose administration showing favourable oral bioavailability.

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