I-BET151 / GSK - LARVOL DELTA

Differential BET protein recruitment to IL6 and IL8 promoters and suppression of inflammatory and cell cycle genes by BET inhibitor in keratinocytes. (PubMed, J Invest Dermatol) - "New evidence for BRD4/p65 enrichment at the IL-6 promoter indicated BRD4 may be a critical factor in integrating inflammatory stimuli via NF-κB in cutaneous inflammation. Inhibition of these responses by I-BET151 highlighted BET proteins as regulators of keratinocyte innate immune responses and potential therapeutic targets in inflammatory skin disease."

Journal • Dermatology • Immunology • Inflammation • Oncology • Psoriasis • BRD2 • BRD4 • CXCL8 • IL17A • IL6

A screen of chromatin-targeting compounds identifies TAF1 as a novel regulator of HIV latency. (PubMed, mBio) - "BAY-299 reactivated HIV expression and enhanced the efficacy of established latency-reversing agents, including vorinostat, prostratin, and iBET-151, in cell line models. These findings highlight a previously unrecognized mechanism of HIV latency control and identify TAF1 as a potential therapeutic target for HIV. Understanding how host chromatin regulators contribute to latency is essential for developing strategies that aim to eliminate the persistent HIV reservoir."

Journal • Human Immunodeficiency Virus • Infectious Disease • TAF1

Cell painting and thermal proteome profiling for inference of drug targets and mechanism of action. (PubMed, Mol Syst Biol) - "We validated our method with public TPP datasets for the five compounds (+)-JQ1, I-BET151, Vemurafenib, Crizotinib and Panobinostat, and public Proteome Integral Solubility Alteration (PISA) data for 49 compounds, together with CP data for 5259 drugs on U2OS cells. Finally, we deployed our method to characterize sinomenine, a compound with elusive knowledge of MoA. Our findings revealed novel facets of sinomenine's biological activity and highlight the value of multimodal profiling for chemical biology."

Journal

Multi-Omics profiling identify NNMT in tumor endothelium as a key regulator of CD8⁺ T cell exhaustion via the TGF signaling pathway. (PubMed, Transl Oncol) - "We establish NNMT as a central metabolic-immune hub that orchestrates TGF-β-mediated CD8⁺ T cell dysfunction and endothelial reprogramming in ccRCC."

IO biomarker • Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • BCL2 • CASP3 • CD8 • IL1B • IL6 • NNMT • TGFB1 • TNFA

Parasite-specific essential bromodomain protein TgBDP4 is a key epigenetic reader and a potential drug target for the parasite Toxoplasma gondii. (PubMed, J Biol Chem) - "When the therapeutic potential of TgBDP4 was evaluated using three bromodomain inhibitors, I-BRD9, (+)-JQ1, and I-BET151, we found that I-BRD9, a selective inhibitor of HsBRD9, effectively inhibits TgBDP4 activity at much lower concentrations than HsBRD9. This inhibition occurs through the binding of I-BRD9 to conserved key residues of the acetyl-lysine-binding pocket of TgBDP4, resulting in a complete arrest of parasite replication in culture and extending the survival time of infected mice. Overall, this study highlights the indispensable role of TgBDP4-mediated gene regulation for parasite survival, establishing TgBDP4 as a promising drug target for treating toxoplasmosis."

Journal • Infectious Disease

Chemotherapeutic Agent-Loaded Nanoparticles Synergizing with X-ray Irradiation to Regulate Fibroblast-like Synoviocytes for Rheumatoid Arthritis Treatment. (PubMed, ACS Nano) - "Herein, we rationally constructed a nanosystem that consists of gold nanoparticles serving as both drug carriers and radiosensitizers, fibroblast activation protein inhibitor (FAPI) as a targeting ligand for pathological neovascularization, and β-cyclodextrin (β-CD) as a host matrix for encapsulating BET inhibitor I-BET151...Combined with low-dose radiotherapy, comprehensive transcriptome standardization and cellular remodeling in RA were achieved. Therefore, our strategy holds considerable promise for advancing the management of rheumatoid arthritis and offers a potent therapeutic modality for refractory RA."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • HIF1A

BRD4 inhibitor I-BET151 sensitizes glioblastoma to radiotherapy by suppressing super-enhancer-driven COL1A1 (AACR 2025) - "In conclusion, I-BET151 enhances radiosensitivity in GBM cells by blocking RT-induced SE-activation and COL1A1 expression, thereby amplifying DNA damage and apoptosis. Further validation in orthotopic GBM models is essential to advance the clinical translation of this promising combination therapy."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • BRD4 • COL1A1

Restraining SRD5A1 combined with BRD4 inhibitor delaying prostate cancer progression by decreasing AR expression. (PubMed, Int J Biol Macromol) - "Bioinformatic analysis revealed that SRD5A1, a critical enzyme in androgen metabolism, is downregulated by the BRD4 inhibitor JQ1. This finding was validated using I-BET151, another BRD4 inhibitor, which also suppressed SRD5A1 expression in PCa cell lines. Furthermore, treatment with dutasteride (Duta), an SRD5A family inhibitor, significantly reduced both cell proliferation and invasion...Co-administration of BRD4 and SRD5A1 inhibitors yielded a more pronounced suppression of AR expression. These findings highlight the pivotal role of SRD5A1 in PCa progression and suggest that combinatorial inhibition of BRD4 and SRD5A1 may provide a more effective strategy for attenuating AR expression and halting disease development."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • BRD4 • SRD5A1

I-BET151 modulates NLRP3 inflammasome-mediated pyroptosis and exhibits anti-inflammatory activity. (PubMed, Sci Rep) - "In vivo experiments demonstrated that I-BET151 exhibited promising therapeutic effects in both DSS-induced acute colitis and CLP-induced SALI models in mice. In conclusion, I-BET151 is a promising candidate for the treatment of colitis and acute lung injury, primarily exerting its biological activity through the targeting of NLRP3 protein."

Journal • Acute Lung Injury • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Inflammatory Bowel Disease • Respiratory Diseases • Septic Shock • IL1B • NLRP3

The Resistance Mechanism to BET-Protac in Multiple Myeloma (ASH 2023) - "AR1 and AR2 cells showed decreased sensitivity to ARV-825, MZ-1, OTX-015, I-BET151, Daunorubicin and Epirubicin...Combined use of ABCB1 inhibitors (verapamil, cyclosporin A, Elacridar) or knockout of ABCB1 could significantly reduce the IC50 of drug-resistant cells, increase the apoptosis rate after ARV-771 treatment, and increase the degradation of BRD4 and the down-regulation of c-Myc... Our results showed that BET-PROTAC resistance in MM cells wasindependent of β-catenin activation. The up-regulation of ABCB1 expression was the key mechanism mediating the resistance of myeloma cells to BET-PROTAC. C1orf112, CCDC167 and CRIP2 might be associated with drug resistance in myeloma and could affect prognosis, and their mechanisms in myeloma need to be further investigated."

Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • ABCB1 • BRD4 • MYC • TCF7

Inferring residue level hydrogen deuterium exchange with ReX. (PubMed, Commun Chem) - "Using ReX, we analyze the differential flexibility of BRD4's two Bromodomains in the presence of I-BET151 and quantify the conformational variations induced by a panel of seventeen small molecules on LXRα. Our analysis reveals distinct residue-level HDX signatures for ligands with varied functional outcomes, highlighting the potential of this characterisation to inform mode of action analysis."

Journal • BRD4

BRD4 inhibition sensitizes glioblastoma to radiotherapy by suppressing super-enhancer-driven COL1A1. (PubMed, Oncogene) - "We aimed to explore the synergistic efficacy of the bromodomain-containing protein 4 (BRD4) inhibitor I-BET151 in combination with RT for GBM therapy...In conclusion, BRD4 contributes to extracellular matrix remodeling and radioresistance in a SE-driven COL1A1-dependent manner. Thus, targeting BRD4 is a rational strategy to augment the efficacy of RT for GBM treatment."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • BRD4 • COL1A1

REGULATION OF COL1A1 BY BRD4 CONDENSATES IN HEPATIC STELLATE CELLS (AASLD 2025) - "Immortalized HSCSs (LX-2) were treated with I-BET151, a bromo and extra-terminal (BET) family of transcriptional regulators inhibitor before stimulation with TGFβ... These findings propose a novel model of pathological COL expression, whereby BRD4 transcriptional condensates are formed in response to TGFβ stimulation to modulate the expression of pathological COL1A1. Thus, specific condensate targeting may be a therapeutic approach for treating liver fibrosis."

Fibrosis • Hepatology • Immunology • Liver Cirrhosis • BRD4 • COL1A1 • TGFB1

LIVER SINUSOIDAL ENDOTHELIAL CELL INTERCELLULAR ADHESION MOLECULE 1 (ICAM1) PROMOTES LIVER INFLAMMATION IN METABOLIC DYSFUNCTION-ASSOCIATED STEATOHEPATITIS (AASLD 2025) - "Furthermore, BET protein pan inhibitor iBET151 suppressed PA-induced upregulation of LSEC ICAM1 and proinflammatory chemokines in vitro and ex vivo models of lipotoxicity and MASH... LSEC ICAM1 is epigenetically upregulated during lipotoxicity via a GSK3β/c-Jun/BRD4 dependent mechanism and enhances myeloid cells adhesion. ICAM1 inhibition is salutary in murine MASH and might serve as a potential therapeutic target in human MASH."

Fibrosis • Hepatology • Immunology • Inflammation • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • BRD4 • CD68 • ELANE • ICAM1 • JUN

Development and Validation of an HPLC-MS/MS Method for Determining I-BET151 in Rat Plasma and Its application to Pharmacokinetic Studies. (PubMed, Drug Des Devel Ther) - "The pharmacokinetic results displayed that the half-life of oral and intravenous administration of I-BET151 was 4.3 h and 3.1 h, respectively. The oral bioavailability was about 60%, indicating that I-BET151 had a high oral bioavailability and appropriate half-life, demonstrating good clinical application prospects."

Journal • PK/PD data • Preclinical • Chronic Graft versus Host Disease • Graft versus Host Disease • Immunology

I-BET151 modulates glucokinase gene expression and beta cell function in part through changes in FOXO1 expression. (PubMed, Diabetologia) - "The results presented here suggest that BET inhibition therapy should be used with caution due to possible bimodal effects at high concentrations at the detriment of pancreatic beta cell function."

Journal • Diabetes • Immunology • Metabolic Disorders • Oncology • Solid Tumor • Type 1 Diabetes Mellitus • FOXO1 • HNF1A

Upregulation of PRSS27 driven by super-enhancers attenuates oxidative stress and apoptosis via activating PI3K/AKT pathway in lung adenocarcinoma. (PubMed, Life Sci) - "Functional assays demonstrated that inhibition of SEs (JQ-1 and i-BET151) suppressed LUAD cell viability, proliferation, and colony formation while promoting apoptosis. Notably, rescue assays showed that PRSS27 overexpression effectively mitigated inhibitor-induced oxidative stress and apoptosis of SEs. Collectively, these findings identify SE-driven activation of PRSS27 as a novel oncogene that promotes LUAD progression by modulating PI3K/AKT signalling pathway, highlighting its potential as a therapeutic target."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Unique cellular signatures and HIV transcripts identified in CD4 lymphoid T cells - HOPE Act organ transplantation collaboration (IAS-HIV 2025) - "For transcriptional changes following LRA treatment, CD4+ T cells were isolated from lymph nodes in 6/24 samples and were stimulated for 24 hours with LRA combinations (VOR+AZD5582, VOR+AZD5582+IL-15 and VOR+AZD5582+IL-15+iBet-151) prior to single cell RNA sequencing (scRNAseq). Using scRNA analysis of a total 94,716 cells we identified 57 cells with HIV transcripts most of which mapped to viral LTR. Lymph nodes obtained from PLWH undergoing solid organ transplantation represent a high yield source for deep lymphatic tissue. We identified LRA-induced HIV reactivation and defined effects of LRA combinations on transcriptomic profiles of tissue resident CD4 T cells. This data can be used to evaluate future LRAs and assess their combination efficacy and their ability to unmask the lymphatic reservoir."

Human Immunodeficiency Virus • Infectious Disease • Solid Organ Transplantation • Transplantation • CD4 • IL15

Partitioning of the functional contributions of Stat3 and Myc to gastric tumour development in mice (EACR 2025) - "We ablated Myc in tumour-bearing compound mutant Gp130F/F; Myc(flox) mice, which also harboured a tamoxifen-inducible Cre under the transcriptional control of either the Tff1 or the gpA33 locus to limit recombinase activity to the gastric epithelium (Thiem et al, Cancer Res 2016; Stuart et al, Mol Cancer Ther 2014)...Likewise, Myc inhibition using the Brd4-antagonist iBET-151 reduced the number of Ki67+ proliferating tumour cells and conferred therapeutic benefits to tumour-bearing Gp130F/F mice... Our observations suggest that partitioning of Stat3 responses into their Myc dependencies informs about the suitability of emerging Myc-antagonists to control Stat3-driven tumors that lack current clinical alternatives to specifically inhibit Stat3."

Late-breaking abstract • Preclinical • Gastric Cancer • Oncology • Solid Tumor • BRD4 • MYC • STAT3 • TFF1

A screen of chromatin-targeting compounds identifies TAF1 as a novel regulator of HIV latency. (PubMed, bioRxiv) - "BAY-299 reactivated HIV expression and enhanced the efficacy of established latency-reversing agents (LRAs), including vorinostat, prostratin, and iBET-151, in cell line models. These findings highlight a previously unrecognized mechanism of HIV latency control and identify TAF1 as a potential therapeutic target. Understanding how host chromatin regulators contribute to latency is essential for developing strategies that aim to eliminate the persistent HIV reservoir."

Journal • Human Immunodeficiency Virus • Infectious Disease • TAF1

ENDOTHELIAL BRD4 DRIVES INFLAMMATORY MACROPHAGE INFILTRATION VIA TIMP1-MEDIATED ANGIOCRINE SIGNALING DURING LIVER FIBROSIS (DDW 2025) - "Primary human LSECs were treated with TNFα and BRD4 inhibitor iBET151, with these samples subsequently utilized for ChIP-seq analysis...SE-induced TIMP1 expression is dependent on BRD4. Inhibition of the SE activity of TIMP1 by LSEC-BRD4 deletion alleviates liver inflammation and fibrosis."

Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • BRD4 • CD63 • CDH5 • TIMP1 • TNFA

Liver sinusoidal endothelial cell BRD4 drives inflammatory angiocrine signaling in liver fibrosis (EASL 2025) - "Primary human LSECs were treated with TNFα and BRD4 inhibitor iBET151, with these samples subsequently utilized for ChIP-seq analysis... LSEC-derived TIMP1 facilitates the recruitment of CD63+ BMDMs, thereby promoting liver inflammation. SE-induced TIMP1 expression is dependent on BRD4. Inhibition of the SE activity of TIMP1 by LSEC-BRD4 deletion alleviates liver inflammation and fibrosis."

Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • BRD4 • CD63 • CDH5 • TIMP1 • TNFA

Efficacy and Toxicity Analysis of Selective BET Bromodomain Inhibitors in Models of Inflammatory Liver Disease. (PubMed, J Med Chem) - "Our results show that pan-D1-biased + BRD4-D2 inhibitor, 3, is as efficacious as pan-BET inhibitor, I-BET151, in reducing inflammation in both models, whereas pan-D2 inhibitors are less effective...Finally, BRD4-D1 selective inhibitors are better tolerated in a preclinical thrombocytopenia model than 3, while gastrointestinal toxicity may be a BRD4-driven effect. These results highlight the importance of assessing specific BET bromodomain functions due to their diverse roles in disease models."

Adverse events • Journal • Gastrointestinal Disorder • Hematological Disorders • Hepatology • Inflammation • Thrombocytopenia • BRD4

Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal. (PubMed, Elife) - "Combining latency reversal agents (LRAs) with differing mechanisms of action such as AZD5582, a non-canonical NF-kB activator, and I-BET151, a bromodomain inhibitor is appealing toward inducing HIV-1 reactivation. Moreover, knockout of INTS12 increased HIV-1 reactivation in CD4 T cells from virally suppressed PLWH ex vivo, and we detected viral RNA in the supernatant from CD4 T cells of all three virally suppressed PLWH tested upon INTS12 knockout, suggesting that INTS12 prevents full-length HIV RNA production in primary T cells. Finally, we found that INTS12 more generally limits the efficacy of a variety of LRAs with different mechanisms of action."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Discovery of 4,5-dihydro-benzo[g]indazole-based hydroxamic acids as HDAC3/BRD4 dual inhibitors and anti-tumor agents. (PubMed, Eur J Med Chem) - "Guided by scaffold hopping strategy, key pharmacophore of BRD4 inhibitor I-BET-151 was incorporated into an in-house developed HDAC3-selective inhibitor 17h...Compound 26n demonstrated significant antitumor efficacy in Capan-1 CDX model, with a tumor growth inhibition rate of 71 % under the given dosing regimen. In summary, this research highlights the promising therapeutic potential of benzodihydroindazole derivatives as HDAC3/BRD4 dual inhibitors, warranting further investigation."

Journal • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • BRD4 • HDAC3 • MYC