EPZ004777 / BMS, Ipsen - LARVOL DELTA

DOT1L/menin inhibitors target replication fork plasticity and create novel vulnerability to PARP inhibitor in MLL-rearranged AML (ASH 2025) - "To this end, our studyaims to better understand the leukemia suppressive functions of DOT1L/MENIN inhibitors and therebyfacilitate the rational development of more effective treatments.To identify key pathways commonly affected by inhibitors targeting DOT1L/MENIN complexes, weperformed RNA-seq on both primary MLL-AF9 AML derived from mouse hematopoietic stem/progenitorcells (HSPCs) and human MLL-r AML cell line MV4; 11 with or without DOT1Li (EPZ004777) or MENINi (MI-503). While single treatments with PARPi, DOT1Li, or MENINi exhibited no ormoderate effects on disease progression, combo treatments in particular MENINi+PARPi significantlyprolonged the disease latency with all animals remaining disease-free at the experimental endpoint. Taken together, these data reveal that DOT1L/MENIN inhibition alter replication fork plasticity and inducea novel vulnerability that can be therapeutically targeted by PARP inhibition for effective leukemiatreatment."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • DOT1L • MEIS1

DIRECT FUNCTIONAL HOXA9/DNA BINDING COMPETITORS VERSUS EPIGENETIC INHIBITORS OF HOXA9 EXPRESSION ON CELL PROLIFERATION, DEATH AND DIFFERENTIATION PROCESSES IN THE MODEL OF MLL-REARRANGED ACUTE MYELOID LEUKAEMIA (EHA 2025) - "For this purpose, we first focused on genes and pathways that were deregulated, utilizing transcriptomic data to identify both shared and distinct deregulated pathways across the approaches and then evaluated cellular effects based on global cell survival and further identified the impact of cell death, cell cycle and cell differentiation using direct HOXA9/DNA binding competitors (HOXA9i) or epigenetic MLL inhibitors of HOXA9 (Revumenib, MI-503, MM-102, Pinometostat/EPZ5676 and EPZ004777).The present work highlights common and different features from transcriptomic analysis following direct or indirect HOXA9 inhibition. In summary, the use of direct HOXA9 functional inhibitors that target the DNA binding domain, such as DB1055 and DB818, seems to be more effective in promoting differentiation of MLL-r cells compared to the epigenetic MLL inhibitors that operate at the level of HOXA9 expression. This observation offers compelling justification for advancing clinical..."

Epigenetic controller • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD14 • CD40 • CD86 • CDKN1A • DOT1L • HOXA9 • IL1B • ITGAM • KMT2A • WDR5

Exploring the Therapeutic Potential of the DOT1L Inhibitor EPZ004777 Using Bioinformatics and Molecular Docking Approaches in Acute Myeloid Leukemia. (PubMed, Curr Issues Mol Biol) - "EPZ004777 has been identified as a potent modulator of SNX19, TPBG, and ZNF185 associated with apoptosis and tumor progression in AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • DOT1L • NPM1 • TPBG

DOT1L regulates cellular senescence during the progression from acute kidney injury to chronic kidney disease via the micro-222-5p/WNT9B signaling pathway. (PubMed, Am J Nephrol) - "DOT1L regulates cellular senescence through the miR-222-5p/WNT9B pathway in AKI. These findings suggest that DOT1L may serve as a potential therapeutic target to mitigate the progression of AKI to chronic kidney disease."

Journal • Acute Kidney Injury • Chronic Kidney Disease • Fibrosis • Immunology • Nephrology • Renal Disease • DOT1L • MIR222

The prognostic value and immunological role of calcium/calmodulin dependent protein kinase kinase 2 (CAMKK2) in pan-cancer study. (PubMed, Medicine (Baltimore)) - "Additionally, we identified potential regulators of CAMKK2 expression, including miRNAs such as miR.129.1.3p, as well as small-molecule drugs such as EPZ004777, which significantly correlated with CAMKK2 expression...Furthermore, in the kidney renal clear cell carcinoma IMvigor210 cohort, patients ongoing immunotherapy with higher CAMKK2 expression experienced a significantly longer median overall survival, but it was observed that in bladder urothelial carcinoma GSE176307 and skin cutaneous melanoma GSE78220 cohorts, CAMKK2 might significantly prolong overall survival. Briefly, CAMKK2 emerges as a promising molecular biomarker that holds potential implications for prognostic evaluation and predicting the effectiveness of immunotherapy across cancers."

Biomarker • IO biomarker • Journal • Pan tumor • Bladder Cancer • Clear Cell Renal Cell Carcinoma • Cutaneous Melanoma • Endometrial Cancer • Melanoma • Oncology • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer • Uterine Cancer • CAMKK2

The epigenetic enzyme DOT1L histone methyltransferase links oxidative stress, inflammation and fibrosis in diabetic kidney (ECP 2024) - " Male non-diabetic and streptozotocin-induced diabetic C57BL/6J mice were treated with 5 mg/kg EPZ004777 (DOT1L inhibitor) or vehicle, for 4 weeks... Alterations in histone methylation-based epigenetic mechanisms contribute to persistent transcriptional changes associated with a pro-oxidant, pro-inflammatory and pro-fibrotic phenotype of diabetic kidney. DOT1L is likely to promote long-lasting transcriptional effects, since no specific histone demethylase exists to counteract DOT1L-induced H3K79 methylation, an epigenetic imprint of active gene expression. The findings of our study suggest that DOT1L pharmacological targeting could become an important supportive therapeutic strategy to attenuate oxidative stress, inflammation and the excess synthesis of ECM proteins in DKD."

Epigenetic controller • Oxidative stress • Chronic Kidney Disease • Diabetic Nephropathy • Fibrosis • Immunology • Inflammation • Metabolic Disorders • Nephrology • DOT1L • ICAM1 • VCAM1

A cellular senescence-related signature for predicting prognosis, immunotherapy response, and candidate drugs in patients treated with transarterial chemoembolization (TACE). (PubMed, Discov Oncol) - "This study constructed a cellular senescence-related signature that could be used to predict HCC patients' responses to and prognosis after TACE treatment, aiding in the development of personalized treatment plans."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • CDK1 • CHEK1 • FOXM1 • SERPINE1

Histone methyltransferase DOT1L mediates NLRP3 inflammasome priming and activation in atherosclerotic apolipoprotein E knockout mice; potential functional implication in human atherosclerosis (ECP 2023) - "ApoE-/- mice fed a normal/atherogenic diet were treated with 5 mg/kg EPZ004777, a specific DOT1L inhibitor, or vehicle, for 4 weeks...We provide evidence that DOT1L contributes to NLRP3 inflammasome priming and activation in both in vivo and in vitro experimental settings of atherosclerosis. The data point to DOT1L as a promising therapeutic target to reduce inflammation in atherosclerosis."

Epigenetic controller • Preclinical • Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • APOE • DOT1L • IL18 • IL1B • NLRP3

DOT1L regulates MTDH mediated angiogenesis in triple-negative breast cancer: Intermediacy of NF-κB-HIF1α axis. (PubMed, FEBS J) - "Moreover, the condition media (CM) obtained from MDA-MB-231 cells stably expressing either MTDH-Wt or MTDHΔ7 treated with EPZ004777 or Bay-11-7082 (NF-κB inhibitor) or FM19G11 (HIF1α inhibitor) significantly inhibited MTDH-induced tube formation in HUVECs, rat aortic ring sprouting, and vessel formations by CAM assay mimicking physiological angiogenic vasculature. Collectively, our findings reveal a novel epigenetic regulation of MTDH by DOTL1, which drives angiogenesis, and that the therapeutic disruption of the DOT1L-MTDH-NF-κB-HIF1α axis may have usefulness in the management of TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • DOT1L • HIF1A • MTDH

Identification of EPZ004777 and FG2216 as inhibitors of TGF-β1 induced Treg cells by screening a library of epigenetic compounds. (PubMed, Life Sci) - "EPZ004777 and FG-2216 have been identified as potent epigenetic modulators that can reverse TGF-β1 induced T regulatory cells and may be used to treat diverse immune disorders."

Journal • Immunology • CD4 • FOXP3 • IFNG • TGFB1

Synthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides. (PubMed, J Med Chem) - "The compounds 22 and (-)-53 (MU1656), carbocyclic C-nucleoside analogues of the natural nucleoside derivative EPZ004777, and the clinical candidate EPZ5676 (pinometostat) potently and selectively inhibit DOT1L in vitro as well as in the cell. The most potent compound MU1656 was found to be more metabolically stable and significantly less toxic in vivo than pinometostat itself."

Journal • Hematological Disorders • Hematological Malignancies • Oncology • DOT1L

Disruptor of telomeric silencing 1-like promotes ovarian cancer tumor growth by stimulating pro-tumorigenic metabolic pathways and blocking apoptosis. (PubMed, Oncogenesis) - "Pharmacological inhibition of DOT1L (EPZ-5676, EPZ004777, and SGC0946) or genetic inhibition of DOT1L attenuates the growth of ovarian cancer cells in cell culture and in a mouse xenograft model of ovarian cancer. DOT1L inhibition also resulted in the upregulation of the NKG2D ligand ULBP1 and subsequent increase in natural killer (NK) cell-mediated ovarian cancer eradication. Collectively, our results demonstrate that DOT1L promotes ovarian cancer tumor growth by regulating apoptotic and metabolic pathways as well as NK cell-mediated eradication of ovarian cancer and identifies DOT1L as a new pharmacological target for ovarian cancer therapy."

Journal • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • DOT1L • NKG2D

Dot1l Aggravates Keratitis Induced by Herpes Simplex Virus Type 1 in Mice via p38 MAPK-Mediated Oxidative Stress. (PubMed, Oxid Med Cell Longev) - "Inhibition of Dot1l with EPZ004777 (EPZ) alleviated corneal injury, including oxidative stress and inflammation in vivo...Our results demonstrated that the inhibition of Dot1l alleviated corneal oxidative stress and inflammation by inhibiting ROS production through the p38 MAPK pathway in HSK. These findings indicated that Dot1l might be a valuable therapeutic target for HSK."

Journal • Corneal Abrasion • Herpes Simplex • Immunology • Inflammation • Keratitis • Ocular Inflammation • Ophthalmology • DOT1L

Silencing or inhibition of H3K79 methyltransferase DOT1L induces cell cycle arrest by epigenetically modulating c-Myc expression in colorectal cancer. (PubMed, Clin Epigenetics) - "Our results show that DOT1L epigenetically promotes the transcription of c-Myc via H3K79me2. DOT1L silencing or inhibition induces cell cycle arrest at S phase. DOT1L is a potential marker for colorectal cancer and EPZ004777 may be a potential drug for the treatment of colorectal cancer."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor