GSK1324726A / GSK - LARVOL DELTA

Leveraging Tumor-Trained T Cells for Enhanced Melanoma Immunotherapy (SITC 2025) - "Here, we present a novel strategy to enhance the tumor-targeting capacity of autologous T cells through ex vivo education using small-molecule-treated melanoma cells.Methods Murine B16 melanoma cells were treated with small molecules (I-BET726, JQ1, C-170) to enhance tumor immunogenicity, then irradiated and co-cultured with mouse splenocytes in the presence of GM-CSF and CpG-A. (A) Low burden: B16 (1×104) + trained splenocytes (1×107) simultaneously lead to strong tumor reduction. (B) High burden: B16 (1×105) + splenocytes (1.5×107, Day7) reduce tumor growth at d19"

IO biomarker • Melanoma • Oncology • Solid Tumor • CD4 • CD8 • CSF2 • ENTPD1 • HAVCR2 • IFNG • IL7R • LAG3 • PD-1 • TIGIT • TNFRSF9

Trained autologous cytotoxic T-cells derived from PBMCs or splenocytes for immunotherapy of neuroblastoma. (PubMed, Front Immunol) - "Autologous PBMCs were co-cultured with irradiated tumor cells pre-treated with MYC inhibitors (I-BET726, JQ1) and a STING antagonist (C170) to enhance immunogenicity and train tumor-specific PBMCs. This study provides preliminary evidence supporting the efficacy of a personalized, PBMC-based immunotherapy for neuroblastoma. These findings highlight the potential for further development of this approach as a novel treatment strategy, paving the way for improved clinical outcomes in pediatric oncology."

IO biomarker • Journal • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • HOXB6 • IFNG • PHOX2B • STING • SYP

Humanized Candida and NanoBiT Assays Expedite Discovery of Bdf1 Bromodomain Inhibitors With Antifungal Potential. (PubMed, Adv Sci (Weinh)) - "These assays additionally enable the discovery that BET inhibitor I-BET726 targets both Bdf1 BDs, inhibits the growth of a broad spectrum of Candida species, including antifungal-resistant clinical isolates, and displays efficacy in an invertebrate animal model of infection. These collective findings highlight the promising potential of Bdf1 BD inhibitors as an innovative class of antifungal therapeutics and the pivotal role of yeast-based assay development toward achieving this end."

Journal • Infectious Disease • BRD4

Utilizing trained autologous tumor-specific T-cells for neuroblastoma immunotherapy (SITC 2024) - "Autologous PBMCs were co-cultured with irradiated tumor cells treated with MYC inhibitors I-BET726 and JQ1 to train the PBMCs against the tumor. Biopsies and blood draws were performed at the time of diagnosis as part of standard clinical care. All specimen collection for research purposes of this study was obtained after completion of appropriate consents and assents and was approved by the Institutional Review Board, Children's National Hospital, Washington, DC (Pro00009692)."

CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • HOXB6 • IFNG • MYCN • PHOX2B • SYP

Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development. (PubMed, J Med Chem) - "Schistosomiasis is a disease affecting >200 million people worldwide, but its treatment relies on a single agent, praziquantel. An X-ray crystal structure of I-BET726 bound to the second BRD of SmBRD3 [SmBRD3(2)] enabled rational design of a quinoline-based ligand (15) with an ITC K = 364 ± 26.3 nM for SmBRD3(2). The ethyl ester pro-drug of compound 15 (compound 22) shows substantial effects on sexually immature larval schistosomula, sexually mature adult worms, and snail-infective miracidia in ex vivo assays."

Journal • Infectious Disease • BRD3

BET and CDK Inhibition Reveal Differences in the Proliferation Control of Sympathetic Ganglion Neuroblasts and Adrenal Chromaffin Cells. (PubMed, Cancers (Basel)) - "However, differential effects were observed in response to bromodomain and extraterminal (BET) protein inhibitors (JQ1, GSK1324726A) and to the CDK-7 inhibitor THZ1, with BET inhibitors preferentially affecting chromaffin cells, and THZ1 preferentially affecting neuroblasts. The differential dependence of chromaffin cells and neuroblasts on BET and CDK signaling may indicate different mechanisms during tumor initiation in sympathetic ganglia and adrenal."

Journal • Adrenal Cortex Carcinoma • Endocrine Cancer • Neuroblastoma • Oncology • Solid Tumor • ALK • CDK7 • IGF1

Epigenetic therapy to enhance therapeutic effects of PD-1 inhibition in therapy-resistant melanoma. (PubMed, Melanoma Res) - "Cultured B16F10 cells and human UM cells were treated with the histone deacetylase inhibitor (HDACi) entinostat or BETi JQ1...Co-treatment with the bioavailable BETi iBET726 impaired the immunotherapy effect...Indeed, co-cultures of UM with HLA-matched melanoma-specific tumor-infiltrating lymphocytes (TILs) resulted in higher TIL-mediated melanoma killing when entinostat was added. Further exploration of combined immunotherapy and epigenetic therapy in metastatic melanoma resistant to PD-1 inhibition is warranted."

IO biomarker • Journal • Eye Cancer • Gene Therapies • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • PD-L1