For more than a decade, a class of drugs called BET inhibitors have been tested with great promise in cancer clinical trials. Biologically, it seemed promising. Many cancers rely on oncogenes that ‘bromo-terminal domain and additional terminal domain’ (BET) proteins help activate, so blocking BET proteins should slow tumor growth. This happened often in the lab. For patients, results have been largely disappointing, with limited responses, significant side effects, and no clear way to predict which tumors will respond.
A new study by Freiburg’s Max Planck Institute for Immunobiology and Epigenetics (MPI-IE) offers a possible explanation as to why, and suggests the development of more precise treatments.
Treat the entire protein family as a single target
BET inhibitors were developed to block the shared domain that all BET proteins use to bind to chromatin, the tightly packed complex of DNA and proteins where genes are stored and regulated. Based on the assumption that all BET proteins do roughly the same thing, blocking chromatin binding appeared to be a reasonable strategy to silence the machinery that reads cancer genes.
New research from Asifa Akhtar’s lab reveals a more nuanced picture. Their studies revealed that two important BET proteins of this family, BRD2 and BRD4, play distinct roles at different stages of gene activation. BDR4 drives the step that modern therapies target: releasing RNA polymerase II, an enzyme that directs genes into active transcription. However, BRD2 acts early in the initiation phase, recruiting and organizing the molecular machinery that first initiates transcription.
molecular stage manager
Blocking both BRD2 and BRD4 simultaneously, as is often done with current inhibitors, disrupts two different steps of the same process simultaneously, producing effects that are difficult to predict and highly context-dependent. “Think of gene activation like a stage production. BRD2 sets the stage, assembling the props, costumes, and actors to ensure the preparations go smoothly. BRD2 then sends the ‘start’ signal to the actor, BRD4, to begin acting,” says Asifa Akhtar, who led the study at MPI-IE. “Previous research has focused almost entirely on performance. Our data show that the setup work that was done earlier is just as important for gene activation,” explains Asifa Akhtar.
BRD2 was long considered the less interesting of the two proteins. New research suggests the opposite may be true. One of the characteristics of BRD2 is its response content. The enzyme MOF places specific chemical tags on chromatin, known as histone acetylation. These bookmarks act as a sophisticated labeling system that controls which genes to read on the DNA and tells BRD2 where to start its work. BRD2 has a unique sensitivity to these “bookmarks”. Upon removal of MOF, BRD2 loses its grip on chromatin, whereas other BET proteins are largely unaffected. “This finding supports the model that acetylated chromatin creates a platform that concentrates regulatory proteins like BRD2 and allows them to prime the transcriptional machinery when needed,” says lead author Umut Erdogdu from Akhtar’s lab.
The power of clustering
Beyond this specificity, BRD2 actively organizes the transcriptional machinery at a spatial level, forming dynamic clusters at gene binding sites and concentrating the necessary molecular components at the precise location where transcription needs to be initiated.
To understand the importance of clustering in gene transcription, we removed only the specific parts of BRD2 involved in cluster formation while leaving the rest of the protein intact. ”
Umut Erdogdu, first author
The results were amazing. Although BRD2 was still present in the cell nucleus, transcription was almost completely stopped, as if the entire protein had been deleted. “This shows that clustering is not a side effect, but a functional feature of transcriptional regulation, and like a stage manager, BRD2 ensures that all performers and all equipment are in the right position before the curtain rises,” says Asifa Akhtar.
This discovery reframes what selective and more subtle BET inhibition might look like in the future. Rather than designing drugs that block chromatin reading domains common to all members of the family, distinguishing between the different roles of BRD2 and BRD4 during gene activation may be a promising goal. Understanding these differences may be a step toward more targeted and predictable treatments.
sauce:
Max Planck Institute for Immunobiology and Epigenetics
Reference magazines:
Erdogdu Province, New Province; others. (2026). Histone acetylation-dependent clustering of BRD2 directs transcriptional dynamics. natural genetics. DOI: 10.1038/s41588-026-02533-x. https://www.nature.com/articles/s41588-026-02533-x
