pinometostat (EPZ-5676) / Ipsen - LARVOL DELTA

Histone methyltransferase inhibitors prevent lens opacity in diabetic cataract rats. (PubMed, Biochim Biophys Acta Gen Subj) - "Histone methyltransferases are involved in lens opacity in DC rats by regulating Pikfyve gene expression."

Journal • Preclinical • Cataract • Ophthalmology • H19 • PTH1R • TNFA

Genome-Wide Identification of a Chromatin-Splicing Regulatory Axis Driven by DOT1L in MLL-Rearranged Acute Myeloid Leukemia. (PubMed, Genes (Basel)) - " We performed H3K79me2 ChIP-seq and RNA-seq on primary samples from 24 MLLr AML patients, 4 wild-type MLL AML patients, and 4 healthy bone marrow donors, with matched profiling before and after DOT1L inhibition using EPZ5676...About two-thirds of the common switched events overlapped a local H3K79me2 peak, and an aggregate splicing score derived from these events stratified patients by overall survival in the TCGA-AML cohort, with higher scores associated with shorter survival. These data support a model in which H3K79me2 contributes to alternative splicing regulation in MLLr AML, linking the core epigenetic lesion of this disease to aberrant RNA processing with potential prognostic relevance."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • DOT1L • SRSF2

Integrating single-cell and bulk RNA data to explore the prognostic significance of LIM domain family genes in colorectal cancer and unveil their immune landscape. (PubMed, Transl Oncol) - "The prognostic model we developed, based on LIM domain family genes, contributes to predicting the prognosis of CRC patients and provides preliminary biological evidence for further exploration of its clinical translational potential."

Journal • Colorectal Cancer • Oncology • Solid Tumor • CRYAB • PDGFRA • PLAU • PLS3

Distinct regulation of Wnt signaling and EPZ5676 governs human UiPSM reprogramming via the CDX2/T/TBX6 core axis. (PubMed, Cell Regen) - "Moreover, the interaction between CDX2, T, and TBX6 with Wnt signaling is reciprocal to establish a stable regulatory network that preserves UiPSM identity and stemness. Taken together, this work shows that Wnt/β-catenin signaling coordinates UiPSM reprogramming and maintenance via the CDX2/T/TBX6 axis, which offers new mechanistic understanding of human mesoderm lineage specification and somatic cell reprogramming."

Journal • CDX2 • WNT3A

Targeting DOT1L Epigenetic Moonlighting in MLL-Rearranged Leukemia. (PubMed, Cells) - "However, clinical responses to the first-in-class DOT1L inhibitor pinometostat (EPZ5676) have been modest, attributed to suboptimal pharmacokinetics and, more fundamentally, to the recognition that DOT1L possesses methyltransferase-independent functions that evade catalytic inhibition...However, these findings remain preclinical, and significant challenges including oral bioavailability, potential toxicity, and lack of clinical validation must be addressed before clinical translation. In this review, we provide an overview of the evolving understanding of the biology of DOT1L, discuss existing MLL small molecule therapies, and evaluate current advances in therapeutically targeting DOT1L, with particular focus on the targeted degradation of DOT1L as a promising therapeutic strategy for high-risk KMT2A-r leukemia."

Journal • Review • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • DOT1L • KMT2A

Epigenetic regulator DOT1L controls neuronal amyloid pre-cursor protein expression via the p38 mediated mitochondrial fission-fusion homeostasis axis (PubMed, Zhejiang Da Xue Xue Bao Yi Xue Ban) - "DOT1L maintains normal mito-chondrial fission and functional homeostasis through regulation of the p38 signaling pathway, thereby modulating APP expression."

Journal • Alzheimer's Disease • CNS Disorders • APP • DOT1L • MFN1

Inhibition of Dot1L Histone Methyltransferase Expands Bone Injury-Responsive CXCL12 + Stromal Progenitors. (PubMed, bioRxiv) - "Notably, acute pharmacologic inhibition of Dot1L using the selective H3K79 methyltransferase inhibitor EPZ-5676 similarly enhances early progenitor activation, indicating that reduced Dot1L enzymatic activity is sufficient to modulate regenerative engagement...Consistent with these cellular changes, Dot1L reduction is associated with accelerated early bone formation in vivo. Collectively, these findings position Dot1L as an epigenetic gatekeeper that constrains early progenitor activation during the initial phase of adult skeletal repair."

Journal • CXCL12 • DOT1L • PRRX1

A systems biology approach for identifying targetable vulnerabilities in Ewing sarcoma (AACR 2024) - "These systems biology approaches can identify non-oncogene encoded vulnerabilities in Ewing sarcoma and hold the potential for expanding the number of therapeutic options for tumors driven by untargetable oncoproteins."

Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • AURKB • DOT1L • STAG2

The role of DOT1L in the proliferation and prognosis of gastric cancer. (PubMed, Biosci Rep) - No abstract available

Journal • Gastric Cancer • Oncology • Solid Tumor • DOT1L

Targeting DOT1L to enhance the immune response in ovarian cancer (AACR 2025) - "Importantly, a small-molecule DOT1L inhibitor, Pinometostat, is currently in late-stage clinical trials for other types of cancer...This discovery could potentially pave the way for the development of DOT1L inhibitors for HGSOC to increase anti-tumor immune response in ovarian cancer. The present research indicates that DOT1L inhibitors have the potential to be utilized in the precision medicine strategy for addressing DOT1L-high ovarian cancer patients."

Epithelial Ovarian Cancer • Gynecologic Cancers • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • DOT1L

Multi omics analysis reveals senescence associated genes in metabolic dysfunction associated steatohepatitis related liver cancer and their functional validation. (PubMed, Int J Biol Macromol) - "We highlight the role of SAGs in MRLC. SOD2, ALDH2, MME and IGFBP1 were potential biomarkers and therapeutic targets. EPZ5676 was a potential drug for treating MRLC by targeting these four genes."

Journal • Hepatology • Liver Cancer • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Oncology • Solid Tumor • ALDH2 • IGFBP1 • SOD2

Dual function of DOT1L suppresses tumor cell-intrinsic immunogenicity in hepatocellular carcinoma. (PubMed, Oncogene) - "In turn, we demonstrate that DOT1L loss or treatment with the clinical stage inhibitor EPZ-5676 sensitizes tumors to ICB with increased immune infiltration in mice...TCGA data analysis reveals an inverse correlation between DOT1L expression and IFN signatures across multiple cancer types. These findings provide a rationale for targeting DOT1L to improve tumor immunogenicity and overcome immunotherapy resistance."

IO biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • DOT1L • ZEB1

Development of DOT1L-Targeted Protein Degraders for Treating MLL-r Leukemia. (PubMed, J Med Chem) - "Substantial previous work has developed catalytic inhibitors like pinometostat, which showed limited clinical efficacy...In vivo studies with DOT1L808 showed its ability to achieve complete tumor regression in an orthotopic leukemia model without overt toxicity. These results establish protein degradation as a promising therapeutic strategy for MLL-rearranged leukemias."

Journal • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • DOT1L

Epigenetic enzyme inhibitors targeting DNA, histone, and RNA methylation: Mechanisms and therapeutic applications in cancer. (PubMed, Eur J Med Chem) - "For instance, DNMT inhibitors (e.g., azacitidine, decitabine) can reactivate tumor suppressor genes via demethylation; HMT inhibitors like tazemetostat and EPZ-5676 modulate chromatin structure to exert anti-tumor effects; and RNA methyltransferase inhibitors such as STM2457 disrupt RNA metabolism to suppress tumor growth. Despite encouraging preclinical and clinical results, challenges including toxicity and drug resistance remain obstacles to broader clinical application. This review summarizes recent advances in epigenetic inhibitor development to support the design of safer and more effective targeted cancer therapies."

Journal • Developmental Disorders • Oncology

DOT1L inhibition exerts the anti-tumor effect by activating interferon signaling in breast cancer cells. (PubMed, Clin Epigenetics) - "These findings suggest that the anti-breast cancer effect of DOT1L inhibition is mediated by multiple mechanisms, including activation of innate immune signaling."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • DOT1L • ER • HER-2 • STING

Inhibition of H3K79me2 by DOT1L Inhibitor EPZ5676 Promotes Mouse Embryonic Lung Branching Morphogenesis via Increasing Epithelium Proliferation. (PubMed, FASEB J) - "Notably, in mesenchyme-free cultures, EPZ5676 alone did not influence epithelial morphogenesis but synergistically stimulated epithelial branching in the presence of FGF7. These findings identify H3K79me2 as a potential negative regulator of pulmonary branching morphogenesis and highlight the DOT1L inhibitor EPZ5676 as a promising epigenetic therapeutic molecule for promoting lung development and addressing pulmonary developmental disorders."

Journal • Preclinical • CNS Disorders • Developmental Disorders • Gene Therapies • Psychiatry • DOT1L • FGF7

Variable Response of MLL-Rearranged Leukemia Cell Lines to Combinations of Menin, CDK9 and DOT1L Inhibitors (ASH 2023) - " We performed cell viability experiments on leukemia cell lines (MV4; 11, MOLM13, RS4; 11, THP1, SEM, KOPN8, NOMO1, HL60, ML2) with single, two and three drug combinations using a menin inhibitor (VTP50469), a DOT1L inhibitor (EPZ5676), and a CDK9 inhibitor (AZD4573). Based on our preclinical in vitro findings, the co-inhibition of menin-DOT1L or menin-CDK9 is a promising approach for the treatment of MLL-r leukemia. The varying responses of different MLL-r leukemia cell lines to drug combination treatment indicate that not all cases of MLL-r leukemia will respond uniformly to treatment combinations. Taken together, our data provide a strategy to determine optimal treatment combinations for personalized treatment of MLL-r leukemia."

Preclinical • Hematological Malignancies • Leukemia • Oncology • ANXA5 • CDK9 • DOT1L • GLI2 • ITGAM • KMT2A

The Histone Methyltransferase DOT1L Cooperates with LSD1 to Control Cell Division in Blast-Phase MPN (ASH 2024) - "To validate the synthetic lethal interaction between DOT1L and LSD1 we treated DOT1L-ko cells with Bomedemstat or GSK2879552 and discovered a 100-fold increase in drug sensitivity compared to WT cells (MTS-assay)...Consistent with this observation, treatment of the MPN blast-phase cell lines HEL or SET2 with LSD1-inhibitors in combination with the DOT1L-inhibitor EPZ5676 only showed a modest cooperative effect...This cooperation is caused by orchestrated binding of DOT1L and LSD1 at selected enhancer regions and is independent of DOT1L's enzymatic activity. This non-canonical function of DOT1L in blast-phase MPN provides a strong rationale for the development of targeted protein degraders (PROTACs) of DOT1L to exploit these findings therapeutically."

Epigenetic controller • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • ANXA5 • CDK4 • CDK6 • DOT1L • DUSP6 • JAK1 • JAK2 • KMT2A • YBX1

DOT1L as a Therapeutic Target: Insights into Epigenetic Regulation and Cancer Treatment. (PubMed, Biomol Ther (Seoul)) - "Therapeutic strategies targeting DOT1L using inhibitors, such as EPZ-5676, have shown promise in preclinical and clinical studies, highlighting their potential as versatile targets for precision oncology. This review summarizes the recent findings on DOT1L's involvement in cancer development and its potential as a therapeutic target."

Journal • Review • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • DOT1L • MEIS1

Inhibition of EYA family tyrosine phosphatase activity reveals a therapeutic vulnerability and enhances Menin and DOT1L inhibitor efficacy in KMT2A-rearranged leukemia. (PubMed, Exp Hematol Oncol) - "Furthermore, BBR synergized with the menin-MLL inhibitor VTP50469 and showed additive effects with the DOT1L inhibitor EPZ5676, the latter of which restored BBR sensitivity in previously BBR-unresponsive cells. These findings establish EYA PTP activity as a therapeutic target in MLL-r leukemia, support the use of EYA expression for identifying patients likely to benefit from BBR treatment, and highlight the potential of BBR-based combinations to improve response in this high-risk leukemia subtype."

Journal • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • DOT1L • KMT2A

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

Drug Combination Strategy Could Benefit Thousands of Lymphoma Patients (Technology Networks) - "The researchers at The Institute of Cancer Research (ICR) first knocked out genes in B-cell lymphoma cells, in the presence and absence of tazemetostat, and found that DOT1L is needed to interact with the drug to block cell growth...They discovered that combining tazemetostat with a DOT1L inhibitor drug called pinometostat, that is already in clinical trials, can shrink follicular lymphoma tumors in the lab that have developed resistance to tazemetostat...The researchers then tested the combination in DLBCL cells and found that the new drug combination could also stop tumors from growing in this group of patients...In mice, the drug combination significantly blocked DLBCL tumor growth, with no major side effects."

Preclinical • Diffuse Large B Cell Lymphoma • Follicular Lymphoma

Insights into KMT2A rearrangements in acute myeloid leukemia: from molecular characteristics to targeted therapies. (PubMed, Biomark Res) - "Menin inhibitors (e.g., Revumenib, Ziftomenib) disrupt the Menin-KMT2A interaction, suppressing HOXA/MEIS1 and promoting differentiation. DOT1L inhibitors (e.g., Pinometostat) show promise in combination therapies, while novel approaches like WDR5 inhibitors and PROTAC-mediated degradation are expanding treatment options. Despite progress, challenges remain, including optimizing minimal residual disease monitoring, overcoming resistance, and validating biomarkers. This review emphasizes the imperative to translate molecular insights into personalized therapeutic regimens, offering renewed hope for patients afflicted by this historically refractory malignancy."

Journal • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • DOT1L • KMT2A • MEIS1 • WDR5

Design, synthesis and evaluation of pyrimidinobenzylamide and pyrimidinothiophenamide derivatives as inhibitors of DOT1L and related epigenetic targets DNMT3a, PRMT4 and other HMTs. (PubMed, RSC Med Chem) - "The compounds incorporate an aminopyrimidine moiety coupled to a functionalized aryl based on the structure of published DOT1L inhibitors that have entered clinical trials (EPZ-5676, pinometostat)...We identified compound 19d (IC50 = 8.0 μM) as a DNMT3a inhibitor, and 1n (EC50 = 19.0 μM), 1p (EC50 = 4.8 μM) and 19g (EC50 = 11.0 μM) as PRMT4 inhibitors based on the in silico approach that was employed. The in vitro ADMET profile of the compounds matched with the generally accepted lead-like criteria and encouraged the further optimization of these non-nucleosidic hit compounds."

Journal • Hematological Malignancies • Leukemia • Oncology • DNMT3A • DOT1L • PRMT1

C6TSEDRVAJZ, a combination of small-molecule compounds, induces differentiation of human placental fibroblasts into epithelioid cells in vitro (PubMed, Nan Fang Yi Ke Da Xue Xue Bao) - "The small-molecule compound combination C6TSEDRVAJZ is capable of inducing HPFs into ciEP-Ls under hypoxic conditions with a high induction efficiency."

Journal • Preclinical • CD34 • CDH1 • COL1A1 • GLI3 • KRT18 • KRT18 • KRT19 • PAX8 • S100A4 • SMAD3 • VIM • WT1