BRD4
BRD4 is a reader protein that docks on acetylated DNA packaging and pulls in the machinery that switches growth genes such as MYC on. BET inhibitors such as pelabresib and ZEN-3694 block that docking; in NUT carcinoma the cancer's own driver is a BRD4 fusion.
Overview
BRD4 (chromosome 19p13.12) is a chromatin reader of the BET (bromodomain and extra-terminal) family that binds acetylated histones, stays on chromatin through the cell cycle to preserve epigenetic memory and higher-order chromatin structure, and recruits the P-TEFb elongation complex to promoters and to distal enhancers to drive transcription of signal-inducible genes (UniProt O60885). In OnCo, BET inhibitors include pelabresib (phase 3 in primary myelofibrosis) and ZEN-3694, which binds the bromodomains of BRD2, BRD3 and BRD4 and is being tested in NUT carcinoma, prostate and triple-negative breast cancer; fedratinib carries BRD4 activity alongside JAK2 and FLT3; and NUT carcinoma is driven by a BRD4-NUT fusion, itself a BET protein, that the inhibitors displace from chromatin so the cells differentiate.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
In plain words · BRD4 is a reader protein that docks on acetylated DNA packaging and pulls in the machinery that switches growth genes such as MYC on. BET inhibitors such as pelabresib and ZEN-3694 block that docking; in NUT carcinoma the cancer's own driver is a BRD4 fusion.
- 1 · What it is
BRD4 is a reader protein that docks on acetylated DNA packaging and pulls in the machinery that switches growth genes such as MYC on. BET inhibitors such as pelabresib and ZEN-3694 block that docking; in NUT carcinoma the cancer's own driver is a BRD4 fusion.
- 2 · What goes wrong in cancer
The ZEN-3694 record describes BET inhibitors as blocking the bromodomain proteins that switch on growth genes such as MYC, with objective but short-lived responses in early NUT carcinoma trials of molibresib and birabresib; the epigenetic-reprogramming pathway record lists BET proteins among the chromatin readers hijacked in cancer.
- 3 · How drugs use it
3 products aim at BRD4: small molecules. Transcription factors have no pocket to plug, so drugs either degrade them or block the partner protein they need to dock on DNA.
External identifiers
Biology
The ZEN-3694 record describes BET inhibitors as blocking the bromodomain proteins that switch on growth genes such as MYC, with objective but short-lived responses in early NUT carcinoma trials of molibresib and birabresib; the epigenetic-reprogramming pathway record lists BET proteins among the chromatin readers hijacked in cancer.
- NUT carcinoma (BRD4-NUT fusion)
- Primary myelofibrosis (pelabresib)
- Castration-resistant prostate cancer and triple-negative breast cancer (ZEN-3694 trials)
A second JAK inhibitor for myelofibrosis that works after ruxolitinib fails; it carries a boxed warning for a rare brain toxicity (Wernicke encephalopathy) so thiamine is checked.
Pelabresib is an experimental small-molecule drug from Novartis Pharmaceuticals in phase 3 trials, with its target not yet stated publicly.
ZEN-3694 is a BET inhibitor from Zenith Epigenetics being tested in NUT carcinoma, where the cancer's driving fusion is itself a BET protein, and in prostate and breast cancers.
Notes
top- Prevalence not recorded in this wave: HGNC and UniProt carry no positivity rates and no other source was consulted.
Latest papers
topQuery for this target: (TITLE:"BRD4" OR ABSTRACT:"BRD4" OR TITLE:"BET" OR ABSTRACT:"BET" OR TITLE:"BET bromodomain proteins BRD2, BRD3, BRD4, BRDT" OR ABSTRACT:"BET bromodomain proteins BRD2, BRD3, BRD4, BRDT" OR TITLE:"bromodomain containing 4" OR ABSTRACT:"bromodomain containing 4" OR TITLE:"MCAP" OR ABSTRACT:"MCAP" OR TITLE:"HUNK1" OR ABSTRACT:"HUNK1") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about BRD4, not a curated reading list.
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