OF-1 A chemical probe for BRPF bromodomains

A chemical probe for the bromodomains of the BRPF (BRomodomain and PHD Finger containing) family of proteins (BRPF1/2/3) has been discovered by the SGC.

BRPF1/2/3 are scaffolding proteins assembling HAT complexes of the MOZ/MORF family (MOZ, Ybf2/Sas3, Sas2 and Tip60). MYST complexes have a tetrameric core containing BRPF, the tumour suppressor ING and Eaf6/EPC (enhancer of polycomb)-related scaffold subunits. MYST complexes play crucial roles in DNA repair, recombination and replication as well as transcription activation. MOZ is frequently translocated in AML and is required for HSC proliferation.

OF-1 has been shown to bind to BRPF1B with a KD of 100 nM (ITC), to BRPF2 with a KD of 500 nM (ITC) and to BRPF3 with a KD  of 2.4 uM (ITC). Selectivity against other bromodomains is very good, in general >100-fold. The closest off-target effects are against BRD4 (39-fold selectivity) and TIF1a (50% inhibition at 20 µM in the alphascreen). OF-1 increases thermal stability in the cellular thermal shift assay (CETSA) of full length BRPF1B at 1 µM and  also demonstrates accelerated FRAP recovery at 5 µM in the BRPF2 FRAP assay. It shows modest general cytotoxicity.