molibresib (GSK525762) / GSK - LARVOL DELTA

Machine learning-based diagnostic and prognostic models for breast cancer: a new frontier on the clinical application of natural killer cell-related gene signatures in precision medicine. (PubMed, Front Immunol) - "Furthermore, drug sensitivity analysis indicated that high-risk patients were more sensitive to Thapsigargin, Docetaxel, AKT inhibitor VIII, Pyrimethamine, and Epothilone B, while showing higher resistance to drugs such as I-BET-762, PHA-665752, and Belinostat. This study provides a comprehensive analysis of NRGs in BC and establishes reliable ML-based diagnostic and prognostic models. The findings highlight the clinical relevance of NRGs in BC progression, immune regulation, and therapy response, offering potential targets for personalized treatment strategies."

Biomarker • Gene Signature • IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • CD2 • IL21 • PRDX1 • ULBP2

An MHC-Related Gene's Signature Predicts Prognosis and Immune Microenvironment Infiltration in Glioblastoma. (PubMed, Int J Mol Sci) - "We further propose I-BET-762 and Enzastaurin as potential therapeutic candidates for glioma. In conclusion, the four-gene signature we identified and the corresponding risk score model constructed from it provide valuable tools for the prognosis prediction of glioblastoma multiforme (GBM) and may guide personalized treatment strategies. The least absolute shrinkage and selection operator (LASSO) risk score has demonstrated significant prognostic evaluation utility in clinical GBM patients, bringing potential implications for patient stratification and the optimization of treatment regimens."

Biomarker • Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • FCGR2B • MXRA5 • TNFRSF9 • TNFSF14

SIlencing BRD4 to increase NK cell activity for adoptive cell therapy: a novel self-delivering RNAi approach (ITOC 2025) - "Current BET inhibitors such as JQ1 and molibresib target BRD4 but lack specificity, leading to off-target effects that limit their clinical application...Conclusions Incorporating PH-894 treatment into ex vivo NK cell expansion protocols prior to ACT represents a promising strategy for improving NK cell efficacy. These findings suggest that BRD4 may play an important role in regulating NK cell activity and that its silencing may modulate NK cell function, potentially enhancing their antitumor activity. This study provides a foundation for further exploration of BRD4 as a target for enhancing NK cell-based immunotherapies."

IO biomarker • Oncology • BRD4 • IL2RA • KLRD1 • NCAM1

A high-throughput, microplate reader-based method to monitor in vitro HIV latency reversal in the absence of flow cytometry. (PubMed, Virology) - "We show that HIV reactivation by control LRAs like prostratin and romidepsin is readily detected with dose dependence and with significant correlation and sensitivity to standard flow cytometry. Using this method, we screen 79 epigenetic modifiers and identify CUDC-101, molibresib, and quisinostat as novel LRAs. This microplate reader-based method offers accessibility to researchers in resource-limited regions to work with J-Lat cells and more actively participate in global HIV cure research efforts."

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

The BRD4 Inhibitor I-BET-762 Reduces HO-1 Expression in Macrophages and the Pancreas of Mice. (PubMed, Int J Mol Sci) - "When the bromodomain inhibitor I-BET-762 was used to treat macrophages or mice with pancreatitis, high levels of HO-1 were reduced. This study shows that bromodomain inhibitors can be used to prevent physiological responses to inflammation that promote tumorigenesis."

Journal • Preclinical • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatitis • Solid Tumor • BRD4 • HMOX1 • KRAS • NFE2L2 • PDX1

A high-throughput, microplate reader-based method to monitor in vitro HIV latency reversal in the absence of flow cytometry. (PubMed, bioRxiv) - "We show that HIV reactivation by control LRAs like prostratin and romidepsin is readily detected with dose dependence and with significant correlation and sensitivity to standard flow cytometry...Using this method, we screen 79 epigenetic modifiers and identify molibresib, quisinostat, and CUDC-101 as novel LRAs. This microplate reader-based method offers accessibility to researchers in resource-limited regions to work with J-Lat cells and more actively participate in global HIV cure research efforts. J-Lat T-cell lines are important to HIV cure research but require flow cytometryWe describe a method to work with J-Lat cells using a standard microplate readerThis assay can detect control LRAs similar to flow cytometry and discover new LRAsThis assay allows low-resourced laboratories to contribute to HIV cure research."

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

Unraveling the Role of Bromodomain and Extra-Terminal Proteins in Human Uterine Leiomyosarcoma. (PubMed, Cells) - "Furthermore, inhibiting BET proteins with their small, potent inhibitors (JQ1 and I-BET 762) significantly inhibited the uLMS proliferation dose-dependently via cell cycle arrest. The connections between BET proteins and crucial biological pathways provide a fundamental structure to better understand uterine diseases, particularly uLMS pathogenesis. Accordingly, targeting the vulnerable epigenome may provide an additional regulatory mechanism for uterine cancer treatment."

Journal • Leiomyosarcoma • Oncology • Sarcoma • Solid Tumor • Uterine Cancer • Uterine Corpus Leiomyosarcoma • BRD2 • BRD3 • BRD4

Dose Escalation and Expansion Study of GSK525762 in Combination With Fulvestrant in Participants With Hormone Receptor-positive (HR+)/Human Epidermal Growth Factor Receptor 2 Negative (HER2-) Advanced or Metastatic Breast Cancer (clinicaltrials.gov) - P1 | N=124 | Terminated | Sponsor: GlaxoSmithKline | Phase classification: P1/2 ➔ P1

Phase classification • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR

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

Pharmacological targeting of histone H3K27 acetylation/BRD4-dependent induction of ALDH1A3 for early-phase drug tolerance of gastric cancer. (PubMed, Cancer Res Commun) - "ChIP-PCR and ChIP-seq analyses revealed that histone H3 lysine 27 acetylation was enriched in the ALDH1A3 promoter in 5-Fluorouracil (5-FU)-tolerant persister PDCs. By chemical library screening, we found that the BET inhibitors OTX015/birabresib and I-BET-762/molibresib suppressed DTP-related ALDH1A3 expression and preferentially inhibited DTP cell growth...Combination therapy with 5-FU and OTX015 significantly suppressed in vivo tumor growth. These observations suggest that BET inhibitors are efficient DTP cell-targeting agents for gastric cancer treatment."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • ALDH1A3 • BRD2 • BRD4

Role of bromodomain extra terminal inhibitor (BETi) in combination with radiotherapy for the treatment of NF1-associated malignant peripheral nerve sheath tumor (AACR 2024) - "Mice were segregated into vehicle and I-BET 762 treatment groups and treated with either vehicle or drug for one week before the RT was initiated... Genetic mutations in NF-1-associated MPNST tumors result in susceptibility to BETi treatment. In a PDX model of PRC2 wild-type tumors, BETi treatment resulted in tumor regression and sensitized MPNST xenografts to RT. Combining BETi and RT enhanced tumor death and increased expression of genes associated with DNA damage and apoptosis."

Combination therapy • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • CASP3 • ERCC4 • NF1 • RAD50 • RAD51D • XRCC1

Enhancing selectivity and overcoming tissue-specific toxicity in drug discovery: A novel BET inhibitor with targeted delivery for prostate cancer treatment (AACR 2024) - "We engineered a novel BET-selective chemotype conjugated to a Prostate-Cancer specific targeting component in order to overcome the off-tissue effects of state-of-the-art BET inhibitors.To achieve delivery of the compound, we modified the benzodiazepine (BzD) scaffold of the well-established BET inhibitor I-BET762, conjugating the tertiary amine with a self-immolating motif, allowing for intracellular compound release upon an enzymatic trigger...Moreover, we established the transcriptional rationale for loss of cellular fitness using RNA sequencing, discovering strong down-regulation of solute carriers, depriving cells of nutrient flux and disrupting normal processes.Furthermore, RT53 exhibits antitumor activity in vivo, in localized models of prostate cancer established in male athymic nude mice. The targeted delivery of RT53 demonstrated superior efficacy in vivo ameliorating on-target, off-tissue toxicity, as low-dose treatment led to almost complete elimination of..."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • MYC

BRD4 inhibitors broadly promote erastin-induced ferroptosis in different cell lines by targeting ROS and FSP1. (PubMed, Discov Oncol) - "BRD4 inhibition by JQ-1 and I-BET-762 or BRD4 knockdown resulted in substantial accumulation of reactive oxygen species (ROS) in both HEK293T and HeLa cells. Our results suggest that ROS accumulation and FSP1 downregulation are common mechanisms underlying increased ferroptosis with BRD4 inhibitors. Thus, BRD4 inhibitors might be more effective in combination with ferroptosis inducers, especially in FSP1-dependent cancer cells."

Journal • Preclinical • Oncology • AIFM2 • BRD4 • FTH1 • GPX4 • VDAC3

Inhibition of Bromodomain Proteins Enhances Oncolytic HAdVC5 Replication and Efficacy in Pancreatic Ductal Adenocarcinoma (PDAC) Models. (PubMed, Int J Mol Sci) - "RNAseq analysis demonstrated that the inhibitors increased viral E1A expression, altered expression of cell cycle regulators and inflammatory factors, and attenuated expression levels of tumour cell oncogenes such as c-Myc and Myb. The data suggest that the tumour-selective Ad∆∆ and Ad-3∆-A20T combined with epigenetic inhibitors is a novel strategy for the treatment of PDAC by eliminating both cancer and associated stromal cells to pave the way for immune cell access even after systemic delivery of the virus."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BRD4 • MYC

Cytoplasmic Accumulation of Histones Induced by BET Inhibition Protects Cells from C9orf72 Poly(PR)-Induced Cell Death. (PubMed, Adv Biol (Weinh)) - "Further investigation reveals that BRD4 inhibitors, such as JQ-1 and I-BET762, restrict cytoplasmic localization of PR20, thereby reducing its cytotoxic effect. In addition, phenylephrine (PE) induces cellular hypertrophy and cytoplasmic distribution of histone, which also helps protect cells from PR20-induced cell death. The research suggests that temporarily inducing the presence of cytoplasmic histones may alleviate the neurotoxic effects of dipeptide repeat proteins."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • BRD4

A Phase I/II Study of GSK525762 Combined with Fulvestrant in Patients with Hormone Receptor–positive/HER2-negative Advanced or Metastatic Breast Cancer (Clin Cancer Res) - P1/2 | N=124 | NCT02964507 | Sponsor: GlaxoSmithKline | "The study included 123 patients. The most common treatment-related adverse events (AE) were nausea (52%), dysgeusia (49%), and fatigue (45%). At a 60-mg dosage of molibresib, >90% of patients experienced treatment-related AE. Grade 3 or 4 treatment-related AE were observed in 47% and 48% of patients treated with molibresib 60 mg and molibresib 80 mg, respectively. The ORR was 13% [95% confidence interval (CI), 8–20], not meeting the 25% threshold for proceeding to phase II. Among 82 patients with detected circulating tumor DNA and clinical outcome at study enrollment, a strong association was observed between the detection of copy-number amplification and poor progression-free survival (HR, 2.89; 95% CI, 1.73–4.83; P < 0.0001)."

P1/2 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

A Phase I/II Study of GSK525762 Combined With Fulvestrant in Patients With Hormone Receptor-Positive/HER2-Negative (HR+/HER2-) Advanced or Metastatic Breast Cancer. (PubMed, Clin Cancer Res) - "Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study."

Journal • Metastases • P1/2 data • Breast Cancer • Fatigue • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRD2 • BRD3 • BRD4 • BRDT • HER-2

A Phase I/II Study of GSK525762 Combined With Fulvestrant in Patients With Hormone Receptor-Positive/HER2-Negative (HR+/HER2−) Advanced or Metastatic Breast Cancer (Clin Cancer Res) - P1/2 | N=124 | NCT02964507 | Sponsor: GlaxoSmithKline | "The study included 123 patients....At molibresib 60 mg, >90% patients experienced treatment-related AEs. Grade 3 or 4 treatment-related AEs were observed in 47% and 48% of patients treated with molibresib 60 mg and molibresib 80 mg, respectively. The ORR was 13% (95% CI, 8–20), not meeting the 25% threshold for proceeding to phase II. Among 82 patients with detected circulating tumor DNA and clinical outcome at study enrolment, a strong association was observed between the detection of copy number amplification and poor progression-free survival (hazard ratio, 2.89; 95% CI, 1.73–4.83; P < 0.0001)."

P1/2 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

The role of PTEN and epigenetic kinome programming in EGFR TKI response in glioblastoma (SNO 2023) - "We found that cells expressing Pten were 10-fold more sensitive to multiple BET inhibitors, including JQ1, birabresib, and molibresib, and these inhibitors synergized with neratinib to reduce proliferation only in the Pten wild type model. Ongoing work is focused on defining the role of PTEN in maintenance of differential transcriptional and epigenetic programs. We will explore potential mechanistic roles of both the enzymatic and non-enzymatic functions of Pten and characterize its effect on hallmark cancer phenotypes such as proliferation, stemness/self-renewal, and tumorigenesis in the presence and absence of EGFR ± BET inhibitors."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • PTEN

Fragment expansion with NUDELs - poised DNA-encoded libraries (DELs) (ACS-Fall 2023) - "This method gave an inhibitor with a LLE of 6.4, 4 orders of magnitude higher than benchmark BRD4 compounds i-BET762, and JQ1. Additionally, the activity was shown to arise from the synergistic unique pairing of building blocks, rather than cumulative potency increases from beneficial moieties in isolation and this would not have been possible to identify via another method.This platform delivered the outlined inhibitor lead-compound in weeks and lays the foundations to rapidly accelerate the drug discovery process. We anticipate this to become common practice for the maturation of fragment hits in the future in both academic and industrial drug discovery programmes due to the speed and economy of the method."

BRD4

Clinical outcomes and correlation with longitudinal circulating tumor (ct)DNA dynamics of a phase I/II study of GSK525762 combined with fulvestrant in patients with hormone receptor-positive/HER2-negative (HR+/HER2−) advanced or metastatic breast cancer. (ASCO 2023) - P1/2 | "Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study. Copy number adjusted ctDNA MR is a promising early marker for clinical benefit. Clinical trial information: NCT02964507."

Circulating tumor DNA • Clinical • Clinical data • Metastases • P1/2 data • Breast Cancer • Fatigue • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRD2 • BRD3 • BRD4 • BRDT • HER-2

Phase 1 Study of Molibresib (GSK525762), a Bromodomain and Extra-Terminal Domain Protein Inhibitor, in NUT Carcinoma and Other Solid Tumors. (PubMed, JNCI Cancer Spectr) - "Once-daily molibresib was tolerated at doses demonstrating target engagement. Preliminary data indicate proof-of-concept in NC."

Journal • P1 data • Fatigue • Hematological Disorders • NUT Midline Carcinoma • Oncology • Testicular Cancer • Thrombocytopenia • CCL2

A phase I/II open-label study of molibresib for the treatment of relapsed/refractory hematologic malignancies. (PubMed, Clin Cancer Res) - P2 | "While anti-tumor activity was observed with molibresib, use was limited by gastrointestinal and thrombocytopenia toxicities. Investigations of molibresib as part of combination regimens may be warranted."

Journal • P1/2 data • Acute Myelogenous Leukemia • Cutaneous T-cell Lymphoma • Febrile Neutropenia • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • Thrombocytopenia

Regulation of inflammatory genes in decidual cells: Involvement of the bromodomain and extra-terminal family proteins. (PubMed, PLoS One) - "BET involvement was assessed using the selective BET inhibitors (+)-JQ1 and I-BET-762 or the negative control compound (-)-JQ1. BETs likely act at chromatin loci separate from the examined promoters. BET inhibitors may block decidual activation at labor."

IO biomarker • Journal • Inflammation • BRD2 • CXCL8 • IDO1 • IL10 • IL6 • PACERR • PTGS1 • PTGS2

A phase I/II dose escalation and expansion study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in combination with fulvestrant in subjects with ER+ breast cancer (SABCS 2017) - P2; "Subjects with disease that progressed during treatment with the combination of a CDK4/6 inhibitor plus letrozole for advanced or metastatic disease.Contact Information: Elizabeth Cunningham, Elizabeth.A.Cunningham@GSK.com. NCT02964507"

Combination therapy • P1/2 data • Hormone Receptor Breast Cancer