Discussion

The human BRPF (bromodomain and PHD finger containing) family of histone acyl-lysine reader proteins, BRPF-1, -2, -3, are important regulators of epigenetic signalling. These proteins recognise specific acyl lysine residues on histones, leading to changes in chromatin structure, multi-protein complex formation and transcriptional regulation. This drug target is relatively early wrt target validation although there is an emerging understanding of its potential role in acute myeloid leukemia (AML). The activation of the BRPF1/HOX pathway through MOZ histone acyl transfer is critical for MOZ-TIF2 to induce AML.

In collaboration with the Structural Genomics Consortium (University of Oxford, UK), we have identified a ‘toolbox’ of potent and selective small molecule inhibitors of BRPF1 through optimization of a fragment derived screening hit. A detailed profile of NI-57 as a Chemical Probe for BRPF bromodomains will be presented.

Ultimately, these inhibitors may represent potential starting points for a drug discovery program as a new approach to the treatment of AML and possibly other cancers.