Loading
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.
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.
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.
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.
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 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.
Broadly expressed or essential: HPA lists BRD4 among essential proteins and finds the RNA at low tissue specificity; the 3 medicines aimed at it (Pelabresib, ZEN-3694, Fedratinib) act on the wild-type protein, so normal tissue is exposed and the therapeutic window comes from the tumour's faster division or its dependence on the protein. HPA BRD4: RNA low tissue specificity; high antibody staining in 44 normal tissues; highest cancer staining skin cancer (12 of 12 high). Distribution: 4 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (NUT carcinoma (midline carcinoma with NUTM1 rearrangement), Myeloid neoplasms, Prostate cancer, Breast cancer (all types)); Open Targets associates it with 0 specific cancer types at or above 0.5. (Rule 7 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas BRD4 tissue; Open Targets ENSG00000141867 associations
First described 1997. Earliest sequence paper UniProt cites for the protein: Weber, 1997. Source.
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.
RNA: low tissue specificity, detected in all normal tissues.
Medium: Testis.
HPA BRD4 tissue · HPA BRD4 pathology · HPA protein class: Essential proteins
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
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.
Query 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.
Shares JAK2, Primary myelofibrosis and the tag wave5-target.
Shares JAK2, Primary myelofibrosis and the tag wave5-target.
Shares Transcriptional machinery & addiction, MYC and the tag wave5-target.
Shares Transcriptional machinery & addiction, MYC and the tag wave5-target.
Shares Epigenetic reprogramming, Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET) and the tag wave5-target.
Shares JAK2 and the tag wave5-target.
Shares Transcriptional machinery & addiction and the tag wave5-target.
Shares Epigenetic reprogramming and the tag wave5-target.