pinometostat (EPZ-5676) / Ipsen - LARVOL DELTA

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

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

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

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 • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • ANXA5 • CDK4 • CDK6 • DOT1L • DUSP6 • JAK1 • JAK2 • KMT2A • YBX1

YTHDC1 is a therapeutic target for B-cell acute lymphoblastic leukemia by attenuating DNA damage response through the KMT2C-H3K4me1/me3 epigenetic axis. (PubMed, Leukemia) - "Indeed, with molecular docking and biochemical experiments, we identified EPZ-5676 as a YTHDC1 inhibitor, and combination of EPZ-5676 with Cytarabine (Ara-c) significantly improved the efficacy of chemotherapy in B-ALL mouse models using YTHDC1high primary and lined B-ALL cells. Collectively, YTHDC1 is required for DDR in B-ALL cells by upregulating DDR-related gene expression via stabilizing m6A-modified KMT2C mRNA, thereby leading to increased histone H3K4 methylation, and targeted inhibition of YTHDC1 is a potentially new therapeutic strategy against B-ALL, especially YTHDC1high B-ALL."

Journal • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2C • YTHDC1

CHIR99021 and Brdu Are Critical in Chicken iPSC Reprogramming via Small-Molecule Screening. (PubMed, Genes (Basel)) - " The final optimized iPSC induction system was bFGF (10 ng/mL), CHIR99021 (3 μM), RepSox (5 μM), DZNep (0.05 μM), BrdU (10 μM), BMP4 (10 ng/mL), vitamin C (50 μg/mL), EPZ-5676 (5 μM), and VPA (0.1 mM)...Concurrently, employing a deletion strategy to investigate the functionality of small-molecule compounds during induction, we identified CHIR99021 and BrdU as critical factors for inducing chicken iPSC formation. In conclusion, this study provides a reference method for utilizing small-molecule combinations in avian species to reprogram cells and establish a network of cell fate determination mechanisms."

Journal • BMP4

Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition in KMT2A-Rearranged Acute Lymphoblastic and Myeloid Leukemia. (PubMed, Int J Mol Sci) - "Finally, we demonstrate significant synergy between revumenib and the DOT1L inhibitor pinometostat in KMT2A-rearranged ALL, suggesting that such drug combinations represent a potent therapeutic strategy for these patients. Collectively, our findings underscore the complexity of resistance mechanisms and advocate for precise patient stratification to optimize the use of menin inhibitors in KMT2A-rearranged acute leukemia."

Journal • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • DOT1L • KMT2A • MEN1

ANTILEUKEMIC THERAPY WITH DOT1L INHIBITOR DEPENDS ON NORMAL ACTIVITY OF TRANSCRIPTION FACTORS PU.1 AND C/EBPΑ (EHA 2024) - "1 and C/ebpα in the treatment of MLL-AF9+ AML with a DOT1L inhibitor(DOT1Li, Pinometostat)... MLL-AF9+ AML cells with decreased expression of Pu. 1 are resistant to the treatmentwith DOT1Li, while C/ebpα-KO cells are even more sensitive. This will help to narrow down the DOT1Li targetsand most importantly will help to identify better responders to this targeted therapy, pointing out that not onlymutational profiling but also expression level of these important TFs should be included while makingtreatment decisions."

Acute Myelogenous Leukemia • Gene Therapies • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • DOT1L • GATA2 • HOXA9 • LMO2 • MECOM • MEF2C • MEIS1 • THY1

Pinometostat With Standard Chemotherapy in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia and MLL Gene Rearrangement (clinicaltrials.gov) - P1/2 | N=6 | Terminated | Sponsor: National Cancer Institute (NCI) | Phase classification: P1b/2 ➔ P1/2

Combination therapy • Phase classification • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KMT2A

Characterization of macrophages in head and neck squamous cell carcinoma and development of MRG-based risk signature. (PubMed, Sci Rep) - "Finally, drugs with high sensitivity to HNSCC (such as 5-Fluorouracil, Temozolomide, Carmustine, and EPZ5676) were explored and analyze the malignant characteristics of HNSCC. Malignant features associated with HNSCC include angiogenesis, EMT, and the cell cycle. This study has opened up new prospects for the prognosis, prediction, and clinical treatment strategy of HNSCC."

Biomarker • IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • AQP1 • ITGA5 • MAP3K8 • PIK3R3 • STC1 • TGM2

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

EZH2 as a major histone methyltransferase in PDGF-BB-activated orbital fibroblast in the pathogenesis of Graves' ophthalmopathy. (PubMed, Sci Rep) - "From the total of twelve selective HKMT inhibitors in the library, EZH2, G9a and DOT1L inhibitors, DZNeP, BIX01294 and Pinometostat, respectively, prevented PDGF-BB-induced proliferation and hyaluronan production by GO orbital fibroblasts...Our data is the first to demonstrate that among all HKMTs EZH2 dominantly involved in the expression of myofibroblast markers in PDGF-BB-activated orbital fibroblast from GO presumably via H3K27me3. Thus, EZH2 may represent a novel therapeutics target for GO."

Epigenetic controller • Journal • Endocrine Disorders • Grave’s Disease • Ophthalmology • Thyroid Eye Disease • ACTA2 • DOT1L • EZH2

Loss of RNA-binding protein CELF2 promotes acute leukemia development via FAT10-mTORC1. (PubMed, Oncogene) - "Notably, combination therapy with a mTORC1 inhibitor (Rapamycin) and a MA9/DOTL1 inhibitor (EPZ-5676) reduced the leukemia burden in MLL-AF9 mice lacking Celf2 in vivo. Our study elucidated a novel mechanism by which the CELF2/FAT10-AKT/mTORC1 axis regulates the proliferation of normal blood cells and the development of AML, thus providing potential therapeutic targets for myeloid leukemia suppression."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CELF2

Combined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons. (PubMed, Nat Biotechnol) - "A cocktail of four factors, GSK2879552, EPZ-5676, N-methyl-D-aspartate and Bay K 8644, collectively termed GENtoniK, triggered maturation across all parameters tested, including synaptic density, electrophysiology and transcriptomics. Maturation effects were further validated in cortical organoids, spinal motoneurons and non-neural lineages including melanocytes and pancreatic β-cells. The effects on maturation observed across a broad range of hPSC-derived cell types indicate that some of the mechanisms controlling the timing of human maturation might be shared across lineages."

Journal • CNS Disorders

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

Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged acute lymphoblastic leukemia. (PubMed, Exp Hematol Oncol) - "Concomitantly, these pinometostat-resistant cells showed upregulation of several myeloid-associated genes, including CD33 and LILRB4/CD85k. Taken together, this model comprehensively shows the adaptive potential of KMT2A-rearranged ALL cells upon losing dependency on one of its main oncogenic properties."

Journal • Preclinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • AFF1 • CD133 • CDK6 • DOT1L • HOXA9 • KMT2A • LILRB4 • PROM1

Neointima abating and endothelium preserving - An adventitia-localized nanoformulation to inhibit the epigenetic writer DOT1L. (PubMed, Biomaterials) - "We produced adhesive nanoparticles (ahNP) that could be pen-brushed and immobilized on the adventitia to sustainably release pinometostat, an inhibitor drug selective to the epigenetic writer DOT1L that catalyzes histone-3 lysine-79 dimethylation (H3K79me2)...Consistently, AURKB-selective inhibition reduced IH. Thus, this study presents a prototype nanoformulation suited for open vascular reconstructions, and the new insights into chromatin modulators may aid future translational advances."

Journal • Cardiovascular • Obesity • AURKB • BRD4 • DOT1L

H3K79 methylation promotes rapid growth of Alexandrium pacificum under high light intensity via increased photosynthesis. (PubMed, Sci Total Environ) - "Finally, pharmacological experiments using the H3K79me inhibitor EPZ5676 showed that the expression of the photosynthesis-related gene CP43 was significantly reduced by 2.5-fold and the maximum photochemical quantum efficiency of A. pacificum was reduced by 1.2 to 1.8-fold in HL compared with CT, leading to inhibited growth of A. pacificum. These results suggest that H3K79me plays a role in regulating the rapid growth of A. pacificum and photosynthesis is likely an important regulatory pathway, which is the first to provide epigenetic evidence underlying the formation of toxic red tides from the perspective of H3K79me."

Journal

Neointima Abating Yet Endothelium Preserving-An Adventitia-localized Nanoformulation To Inhibit The Epigenetic Writer Dot1L (VASCULAR DISCOVERY 2023) - "We produced adhesive nanoparticles (ahNP) that could be pen-brushed and immobilized on the adventitia to sustainably release pinometostat, an inhibitor drug selective to the epigenetic writer DOT1L that catalyzes histone-3 lysine-79 dimethylation (H3K79me2)...Consistently, AURKB-selective inhibition also reduced IH. Thus, this study presents a prototype nanoformulation suited for open vascular reconstructions, and the new insights into epigenetic regulators may aid future translational advances."

Cardiovascular • Obesity • AURKB • BRD4 • DOT1L

A Phase Ib/II Study of the Histone Methyltransferase Inhibitor Pinometostat in Combination with Azacitidine in Patients with 11q23-Rearranged Acute Myeloid Leukemia (ASH 2019) - P1/2; "Integrative correlative analyses will include genomics, changes in DOT1L-mediated methylation by H3K79 ELISA, and qPCR of HOXA9 and Meis1. PK studies and azacitidine incorporation and DNA methylation studies will also be performed."

Clinical • Combination therapy • P1/2 data • MLL

High-Density CRISPR Scan Identifies Functional Regions of DOT1L That Mediate Therapeutic Response in MLL-r Leukemia (ASH 2018) - P1; "Furthermore, we identified CRISPR hotspots that coincide with amino acid residues directly contacting the enzymatic substrate S-adenosylmethionine (SAM). Finally, we examined eight clinically observed DOT1L missense mutations in this region (cBioPortal database; 54,510 patients) and foundthree DOT1L-mutant constructs (A591V, G594S and L626P) when expressed in the MLL-AF9 leukemia cells can confer resistance to EPZ5676. These findings suggest the utility of the high-density CRISPR scan for de novoidentification of drug-resistant mutant alleles in the human population, which maydirect future clinical decisions and benefit patients with specific genomic backgrounds."

Acute Myelogenous Leukemia • Biosimilar • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

Establishment and Characterization of a Model of Acquired Resistance to DOT1L Inhibition in KMT2A-Rearranged Acute Lymphoblastic Leukemia Cells (ASH 2022) - "As anticipated, pinometostat-resistant cells displayed a slight cross-resistance to most chemotherapeutic agents currently used in ALL treatments but became remarkably more sensitive toward the BCL-2 inhibitor venetoclax. Also, our model demonstrates that under prolonged pressure of DOT1L inhibition, KMT2A-rearranged ALL cells seem to initiate a reprogramming process that involves the acquirement (or selection) of myeloid-like characteristics, an ability that may be connected to leukemic lineage switches which are not uncommon in KMT2A-rearranged acute leukemias. Hence, our model represents an important tool to study the complex biology of KMT2A-rearranged leukemia, and its existence and availability requires to be shared with the community."

IO biomarker • Preclinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • AFF1 • CD133 • CD38 • CDK6 • DOT1L • GNAQ • HOXA9 • KMT2A • MEIS1 • PROM1 • RUNX2