Structural Basis of Inhibitor Selectivity in the BRD7/9 Subfamily of Bromodomains

Inhibition of the bromodomain containing
protein 9 (BRD9) by small
molecules is an attractive strategy to target mutated SWI/SNF chromatin-remodeling
complexes in cancer. However, reported BRD9 inhibitors also inhibit
the closely related bromodomain-containing protein 7 (BRD7), which
has different biological functions. The structural basis for differential
potency and selectivity of BRD9 inhibitors is largely unknown because
of the lack of structural information on BRD7. Here, we biochemically
and structurally characterized diverse inhibitors with varying degrees
of potency and selectivity for BRD9 over BRD7. Novel cocrystal structures
of BRD7 liganded with new and previously reported inhibitors of five
different chemical scaffolds were determined alongside BRD9 and BRD4.
We also report the discovery of first-in-class dual bromodomain–kinase
inhibitors outside the bromodomain and extraterminal family targeting
BRD7 and BRD9. Combined, the data provide a new framework for the
development of BRD7/9 inhibitors with improved selectivity or additional
polypharmacologic properties.