I-BET151 / GSK - LARVOL DELTA

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

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

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

Triple Combination of MEK, BET, and CDK Inhibitors Significantly Reduces Human Malignant Peripheral Nerve Sheath Tumors in Mouse Models (Clin Cancer Res) - "A high degree of redundancy was observed in the effect of compounds of the same inhibitory class, individually or in combination, and responses matched with TSG inactivation status. The MEKi–BETi (ARRY-162 + I-BET151) co-treatment triggered a reduction in half of the NF1-related MPNST PDOXs and all the sporadic tumors, reaching 65% reduction in tumor volume in the latter. Remarkably, this reduction was further increased in both models combining the three inhibitor classes, reaching 85% shrinkage on average in the sporadic MPNST."

Preclinical • Oncology • Sarcoma

Triple Combination of MEK, BET, and CDK Inhibitors Significantly Reduces Human Malignant Peripheral Nerve Sheath Tumors in Mouse Models. (PubMed, Clin Cancer Res) - "Our results strongly support precision therapies for MPNSTs guided by TSG inactivation status. MEKi-BETi-CDKi triple treatment elicits a significant reduction of human MPNST PDOX."

Journal • Preclinical • Brain Cancer • Genetic Disorders • Neurofibromatosis • Neurofibrosarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CDK4 • CDKN2A • NF1

Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal. (PubMed, bioRxiv) - "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 towards inducing HIV-1 reactivation. Moreover, knockout of INTS12 increased HIV-1 reactivation in CD4 T cells from virally suppressed PLWH ex vivo . We also 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."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

The immunological landscape and silico analysis of key paraptosis regulator LPAR1 in gastric cancer patients. (PubMed, Transl Oncol) - "High LPAR1 expression also correlated with increased sensitivity to compounds, such as BET bromodomain inhibitors I-BET151 and RITA, suggesting LPAR1 as a biomarker for predicting drug activity...These findings suggest that LPAR1 is a critical regulator of paraptosis in GC and a potential biomarker for drug sensitivity and immunotherapy response. This underscores the role of CAFs in mediating tumorigenic effects and suggests that targeting LPAR1 could be a promising strategy for precision medicine in GC."

IO biomarker • Journal • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Microsatellite Instability • Oncology • Solid Tumor • CAFs • FOXP2 • MSI

Effect of BET inhibitors on oral squamous cell carcinoma cell line and its' CD44 positive subpopulation (EACR 2024) - "Despite advancements in OSCC management, survival rates remain suboptimal, and the development of novel anti-neoplastic agents is needed.Material and Methods The study investigated the effects of three BET inhibitors (JQ1, iBET-151, iBET-762) on oral squamous cell carcinoma cell line (SCC-25) and its' CD44 positive subpopulation. Conclusion Results of the study indicate better antitumor effect of BET inhibitors on CD44+ population of tumor cells during prolonged treatment of tumor cells. New investigations should provide more insight into mechanism of action of BET inhibitors on specific oral cancer cells subpopulations."

Preclinical • Oncology • Oral Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD44

BET inhibition sensitizes innate checkpoint inhibitor resistant melanoma to anti-CTLA-4 treatment. (PubMed, Pigment Cell Melanoma Res) - "The BET inhibitor IBET151, combined with anti-CTLA-4, overcame innate ICB resistance however, sequential BET inhibition failed against acquired resistance in mouse models...BET proteins in melanoma may play an oncogenic role by inducing immune suppression and driving T cell dysfunction. The study demonstrates an effective combination for innately unresponsive melanoma patients to checkpoint inhibitor immunotherapy, yet highlights BET inhibitors' limitations in an acquired resistance context."

Checkpoint inhibition • IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • BTLA • CD4 • CD8 • HAVCR2 • LAG3

A macrophage-cell model of HIV latency reveals the unusual importance of the bromodomain axis. (PubMed, Virol J) - "Our results indicate that this model could be used to screen for appropriate LRAs for macrophages and show that HIV latency and reactivation mechanisms in macrophages may be distinct from those of CD4 + T cells."

Journal • Human Immunodeficiency Virus • Infectious Disease • BRD4 • CD4