The discovery of the BRD9 bromodomain inhibitor BI-9564 was recently featured as an ACS Editors’ Choice article in the Journal of Medicinal Chemistry.^1,2 In this study, biophysical assays using a compound fragment library were initially utilized to identify novel chemical scaffolds. This was followed by crystallographic studies that allowed refinement of chemical interactions with bromodomain binding sites. Finally, biochemical assays were used to characterize their in vitro activity, achieving further structural refinement. This led to the discovery of BI-9564, which selectively binds the BRD9 bromodomain with a K_d of 14.1 nM. It less potently binds the BRD7 bromodomain (K_d = 239 nM) and is without effect at other bromodomains, as well as a large panel of kinases and receptors. BI-9564 is cell-permeable, inhibits BRD9 in cells, displays good pharmacokinetics in mice, and reduces tumor burden in a disseminated mouse model of acute myeloid leukemia.

BI-9564 is available from Cayman Chemical as a useful tool for exploring BRD9 bromodomain biology in both in vitro and in vivo models. In addition to offering more than 8,000 catalog products, Cayman also provides structural biology services for drug discovery, ranging from large-scale protein expression and crystallization to homology modeling, ligand-protein crystallography, and biophysical characterization.

References

1. Karim, R.M. and Schonbrun, E. An advanced tool to Interrogate BRD9. J. Med. Chem. 59(10) , 4459-4461 (2016).

2. Martin, L.J., Koegl, M., Bader, G., et al. Structure-based design of an in vivo active selective BRD9 inhibitor. J. Med. Chem. 59(10) 4462-4475 (2016).