{"id":77,"date":"2026-06-26T05:22:21","date_gmt":"2026-06-26T05:22:21","guid":{"rendered":"https:\/\/astinovabiolabs.com\/blog\/?p=77"},"modified":"2026-06-26T05:22:21","modified_gmt":"2026-06-26T05:22:21","slug":"target-profile-brd4-bromodomain-containing-protein-4","status":"publish","type":"post","link":"https:\/\/astinovabiolabs.com\/blog\/target-profile-brd4-bromodomain-containing-protein-4\/","title":{"rendered":"Target profile \u2014 BRD4 (Bromodomain-containing protein 4)"},"content":{"rendered":"\n
Field<\/th>Value<\/th><\/tr><\/thead>
Target name<\/td>Bromodomain-containing protein 4 (BRD4); BET family member (UniProt O60885)<\/td><\/tr>
Gene<\/td>BRD4 \u2014 chromosome 19p13.12; NCBI Gene 23476<\/td><\/tr>
Class<\/td>Epigenetic ‘reader’. BET (Bromodomain & Extra-Terminal) family \u2014 two tandem bromodomains (BD1, BD2) plus an ET domain; paralogues BRD2, BRD3 and testis-specific BRDT. Not an enzyme in the conventional sense (an intrinsic HAT\/atypical-kinase activity is reported but contested).<\/td><\/tr>
Ligands \/ mechanism<\/td>Binds acetyl-lysine marks on histones (H3K27ac; H4K5\/8\/12\/16ac) via conserved bromodomain asparagines; recruits P-TEFb (CDK9\u2013cyclin T1) to phosphorylate RNA Pol II and drive transcriptional elongation. Concentrates at super-enhancers that sustain MYC and other oncogenes.<\/td><\/tr>
Expression<\/td>Ubiquitous; nuclear \/ chromatin-associated; remains bound to chromatin through mitosis (‘epigenetic bookmarking’).<\/td><\/tr>
Function<\/td>Transcriptional co-activator \/ elongation factor coupling histone acetylation to output of growth- and survival-driving genes (notably MYC).<\/td><\/tr>
Disease rationale<\/td>Oncology is the anchor. NUT carcinoma is defined by the BRD4\u2013NUT fusion oncogene (t(15;19)). Hematologic malignancies (AML, myelofibrosis) depend on BRD4 via MYC\/BCL2 and NF-\u03baB-driven cytokine programs; selected solid tumors (castration-resistant prostate cancer; ASCL1-driven SCLC). Targeted DEGRADATION is pursued over occupancy to also remove BRD4’s non-bromodomain scaffolding functions and achieve deeper, more durable knockdown \u2014 a lower-dose \/ wider-therapeutic-window benefit is hypothesised but not yet demonstrated clinically. A separate cardiovascular \/ anti-inflammatory hypothesis (BD2-selective apabetalone) reached Phase 3 but FAILED its primary endpoint.<\/td><\/tr>
Class liability<\/td>Dose-limiting thrombocytopenia is the universal, on-target toxicity of BET inhibitors (BET\/GATA1-dependent suppression of megakaryopoiesis), alongside GI toxicity and fatigue, across structurally distinct agents. BD2-selectivity (ABBV-744, NUV-868, apabetalone) has reduced but not eliminated it. This liability is a core driver of interest in degraders and tumor-selective approaches.<\/td><\/tr>
Approval status<\/td>No BET\/BRD4 inhibitor and no BRD4\/BET degrader is approved anywhere as of June 2026 \u2014 all assets are investigational. Closest to approval: pelabresib (pan-BET inhibitor) in myelofibrosis \u2014 MANIFEST-2 met its spleen-volume endpoint but missed the symptom endpoint and is NOT filed; a leukemic-transformation imbalance prompted a new pivotal trial (MANIFEST-3). The only clinical-stage dedicated BRD4 degrader is RNK05047 (Ranok) \u2014 a chaperone-mediated ‘CHAMP’ degrader, not a PROTAC \u2014 in Phase 1\/2. (Note: vepdegestrant\/ARV-471 is an FDA-filed PROTAC but degrades the estrogen receptor, not BRD4, and is excluded.)<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n

Clinical-stage BRD4 \/ BET agents (inhibitors & degraders)<\/h2>\n\n\n\n
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Compound (code)<\/th>Developer<\/th>Modality<\/th>Route<\/th>Phase \/ status<\/th>Lead indication(s)<\/th><\/tr><\/thead>
Pelabresib (CPI-0610 \/ DAK539)<\/td>Novartis (ex-Constellation \/ MorphoSys)<\/td>Pan-BET inhibitor<\/td>Oral<\/td>Phase 3 active. MANIFEST-2 met spleen endpoint (SVR35 66% vs 35%) but missed symptom endpoint (TSS50); not filed; new pivotal MANIFEST-3 recruiting (2026)<\/td>Myelofibrosis (+ ruxolitinib)<\/td><\/tr>
ZEN-3694<\/td>Zenith Epigenetics<\/td>Pan-BET inhibitor<\/td>Oral<\/td>Phase 2b active; FDA Fast Track (NUT carcinoma, 2025)<\/td>mCRPC (+ enzalutamide); NUT carcinoma<\/td><\/tr>
BMS-986158<\/td>Bristol Myers Squibb<\/td>Pan-BET inhibitor<\/td>Oral<\/td>Phase 1\/2 active (pivoted to myelofibrosis)<\/td>Myelofibrosis; multiple myeloma<\/td><\/tr>
INCB057643<\/td>Incyte<\/td>Pan-BET inhibitor<\/td>Oral<\/td>Phase 1\/2 active (LIMBER program)<\/td>Myelofibrosis \/ MPN<\/td><\/tr>
ABBV-744<\/td>AbbVie<\/td>BD2-selective inhibitor<\/td>Oral<\/td>Phase 1b active (MF, + ruxolitinib\/navitoclax); AML arm terminated. DLTs still thrombocytopenia\/anemia<\/td>Myelofibrosis; mCRPC<\/td><\/tr>
EP31670 (NEO2734)<\/td>Epigenetix<\/td>Dual BET + CBP\/p300 inhibitor<\/td>Oral<\/td>Phase 1 recruiting<\/td>Solid tumors, NUT carcinoma, CMML<\/td><\/tr>
Apabetalone (RVX-208)<\/td>Resverlogix<\/td>BD2-selective inhibitor<\/td>Oral<\/td>Phase 3 completed \u2014 BETonMACE MISSED primary MACE endpoint (HR 0.82, p=0.11); development funding-stalled<\/td>Cardiovascular (post-ACS + type-2 diabetes)<\/td><\/tr>
RNK05047 (CHAMP-1)<\/td>Ranok Therapeutics<\/td>BRD4 degrader \u2014 chaperone-mediated (CHAMP), not a PROTAC<\/td>IV<\/td>Phase 1\/2 recruiting (NCT05487170). Only BRD4-selective degrader in the clinic<\/td>Advanced solid tumors; DLBCL<\/td><\/tr>
Birabresib (OTX-015 \/ MK-8628)<\/td>Oncoethix \u2192 Merck<\/td>Pan-BET inhibitor<\/td>Oral<\/td>Discontinued (~2017) \u2014 limited single-agent efficacy<\/td>NUT carcinoma, AML, DLBCL<\/td><\/tr>
Molibresib (GSK525762)<\/td>GSK<\/td>Pan-BET inhibitor<\/td>Oral<\/td>Discontinued \u2014 modest efficacy, thrombocytopenia ~51%<\/td>NUT carcinoma, NHL, breast<\/td><\/tr>
Trotabresib (CC-90010)<\/td>Celgene \u2192 BMS<\/td>Pan-BET inhibitor (CNS-penetrant)<\/td>Oral<\/td>Discontinued 2024 (strategic) despite documented BBB penetration<\/td>Glioblastoma<\/td><\/tr>
Mivebresib (ABBV-075)<\/td>AbbVie<\/td>Pan-BET inhibitor<\/td>Oral<\/td>Discontinued \u2014 myelofibrosis study halted at n=1; thrombocytopenia<\/td>AML, solid tumors<\/td><\/tr>
NUV-868<\/td>Nuvation Bio<\/td>BD2-selective inhibitor<\/td>Oral<\/td>Discontinued 2024 (risk-benefit; Phase 2 declined)<\/td>Ovarian, pancreatic, mCRPC, TNBC<\/td><\/tr>
RO6870810 (TEN-010)<\/td>Roche<\/td>Pan-BET inhibitor<\/td>SC<\/td>Discontinued \u2014 combo study terminated (immune-related AEs)<\/td>NUT carcinoma, ovarian, TNBC<\/td><\/tr><\/tbody><\/table><\/figure>\n","protected":false},"excerpt":{"rendered":"

Field Value Target name Bromodomain-containing protein 4 (BRD4); BET family member (UniProt O60885) Gene BRD4 \u2014 chromosome 19p13.12; NCBI Gene 23476 Class Epigenetic ‘reader’. BET (Bromodomain & Extra-Terminal) family \u2014 two tandem bromodomains (BD1, BD2) plus an ET…<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[17],"tags":[],"class_list":["post-77","post","type-post","status-publish","format-standard","hentry","category-fda-approved-small-molecules"],"_links":{"self":[{"href":"https:\/\/astinovabiolabs.com\/blog\/wp-json\/wp\/v2\/posts\/77","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/astinovabiolabs.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/astinovabiolabs.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/astinovabiolabs.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/astinovabiolabs.com\/blog\/wp-json\/wp\/v2\/comments?post=77"}],"version-history":[{"count":1,"href":"https:\/\/astinovabiolabs.com\/blog\/wp-json\/wp\/v2\/posts\/77\/revisions"}],"predecessor-version":[{"id":81,"href":"https:\/\/astinovabiolabs.com\/blog\/wp-json\/wp\/v2\/posts\/77\/revisions\/81"}],"wp:attachment":[{"href":"https:\/\/astinovabiolabs.com\/blog\/wp-json\/wp\/v2\/media?parent=77"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/astinovabiolabs.com\/blog\/wp-json\/wp\/v2\/categories?post=77"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/astinovabiolabs.com\/blog\/wp-json\/wp\/v2\/tags?post=77"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}