BET Bromodomain Inhibition in Cancer Therapeutics

The Bromodomain and Extra-Terminal (BET) family comprises epigenetic reader proteins that recognise acetylated lysine residues on histone tails and thereby regulate transcription of key oncogenes such as MYC and BCL-2. Small-molecule inhibitors of BET bromodomains displace these proteins from chromatin, leading to suppression of pro-proliferative gene programmes, induction of differentiation and apoptosis in cancer cells. Although early clinical trials have demonstrated promise in haematological and selected solid tumours, challenges remain in managing dose-limiting toxicities, adaptive resistance and suboptimal pharmacokinetics. Current research focuses on enhancing selectivity, improving metabolic stability and developing rational combination regimens with kinase inhibitors, immune modulators or DNA-damaging agents to potentiate efficacy and circumvent resistance mechanisms.

Research from Nature Portfolio

Recent studies have elucidated the structural basis by which BET fusion oncoproteins drive malignant transcriptional circuits. High-resolution nuclear magnetic resonance and crystallographic analyses of a BRD4–NUT fusion have revealed two discrete transactivation domains that bind the TAZ2 region of the p300 histone acetyltransferase. This bipartite interface provokes allosteric activation of p300 and promotes liquid-like chromatin condensates enriched in acetylated histones and transcriptional machinery. Disruption of either interface impairs condensate formation and abrogates aberrant anti-differentiation gene expression, offering a blueprint for design of inhibitors that selectively target pathogenic BET–coactivator assemblies.

BET Bromodomain Inhibition in Cancer Therapeutics publication trend

The graph below shows the total number of articles in bet bromodomain inhibition in cancer therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Bromodomain: A conserved protein module that recognises ε-N-acetylated lysine residues on histone tails, directing chromatin-associated proteins to specific genomic loci.

BET proteins: A subfamily of bromodomain-containing epigenetic readers (BRD2, BRD3, BRD4, BRDT) that regulate gene transcription by binding acetylated chromatin and recruiting coactivators.

Epigenetic reader: A protein domain that interprets covalent modifications on histones, such as acetylation or methylation, without altering DNA sequence.

Histone acetylation: The enzymatic addition of acetyl groups to lysine residues on histone proteins, typically associated with relaxed chromatin structure and active transcription.

Phase separation: A biophysical phenomenon in which multivalent protein–protein and protein–nucleic acid interactions drive formation of membraneless condensates, concentrating factors to facilitate transcription.

p300: A histone acetyltransferase and transcriptional coactivator that acetylates histone and non-histone substrates to regulate chromatin accessibility and gene expression.

References

1. Bromodomain and extraterminal (BET) proteins: biological functions, diseases and targeted therapy. Signal Transduction and Targeted Therapy (2023).
2. Structural mechanism of BRD4-NUT and p300 bipartite interaction in propagating aberrant gene transcription in chromatin in NUT carcinoma. Nature Communications (2023).
3. A bromodomain-independent mechanism of gene regulation by the BET inhibitor JQ1: direct activation of nuclear receptor PXR. Nucleic Acids Research (2023).
4. Bromodomain and extra-terminal motif inhibitors: a review of preclinical and clinical advances in cancer therapy. Future Science OA (2019).