BRD9

Class

Targeted protein degrader (DCAF16-dependent molecular glue, "Targeted Glue")

Pathway

Bromodomain/ncBAF chromatin-remodeling complex - degradation relieves the myeloid differentiation block in AML cells

BRD9 is a protein subunit of the ncBAF chromatin-remodeling complex, one of several related assemblies (collectively called BAF or SWI/SNF complexes) that reposition and open packaged DNA so that genes can be transcribed. BRD9 contains a bromodomain, a module that recognizes a specific chemical mark on histone proteins and helps anchor the complex at particular genomic locations. In certain cancers, including some forms of acute myeloid leukemia (AML), the ncBAF complex is required to sustain a transcriptional program that keeps leukemic cells in an immature, self-renewing state, blocking their normal maturation into functional blood cells. Removing BRD9 relieves this block and allows the cells to resume differentiation. Rather than using a small molecule that simply blocks the bromodomain's binding pocket, this approach uses a molecular glue: a compound that induces an interaction between BRD9 and a cellular protein-disposal machine, tagging BRD9 for destruction. This eliminates the protein entirely, including any functions unrelated to the bromodomain itself, which a pocket-blocking inhibitor would leave intact. This degradation strategy is being explored across cancers where ncBAF dependency has been identified, with AML as a prominent example given the direct link to differentiation blockade.