NI-57 A chemical probe for BRPF bromodomains

A collaboration between the SGC and University College London (UCL) has resulted in the discovery of NI-57 as a chemical probe for the bromodomains of the BRPF (BRomodomain and PHD Finger) family of proteins (BRPF1/2/3).

BRPF1/2/3 are scaffolding proteins assembling HAT complexes of the MOZ/MORF family (MOZ, Ybf2/Sas3, Sas2, and Tip60). These 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 in transcription activation. MOZ is frequently translocated in acute myeloid leukemia and has an essential role in development and maintenance of hematopoietic stem cells.

NI-57 is a potent inhibitor of the bromodomain of the BRPFs and binds to BRPF1B with a KD of 31 nM (ITC), to BRPF2 with a KD of 108 nM (ITC) and to BRPF3 KD of 408 nM (ITC). NI-57 is very selective against other non-Class IV bromodomains, including the BETs, as measured by both biophysical and biochemical methods. The closest off-target effects are against BRD9 (32-fold selective). NI-57 shows accelerated FRAP recovery at 1 µM in the BRPF2 FRAP assay preventing binding of full-length BRPF2 to chromatin.