MI-503 / Kura Oncology, University of Michigan - 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

Menin-inhibition boosts CAR-T cell therapy against NPM1 mutated and KMT2A-rearranged acute myeloid leukemia (ASH 2025) - "Here, we discovered that men-i uniformly induces the expression of theimmunotarget CLEC12A (also known as CLL-1) on both leukemia entities, thereby sensitizing these cellsfor chimeric antigen receptor (CAR)-based immunotherapy.Initially, RNAseq revealed CLEC12A to be consistently upregulated in KMT2A-r and NPM1m AML cellsupon pharmacological inhibition with different men-i, including MI-503, ziftomenib, or VTP-50469 (closehomologue to revumenib). Combined in vivo men-i (14 days) and CLEC12A-directed CAR-T celltreatment resulted in significantly enhanced eradication of engrafted KMT2A-r MOLM-13 cells asassessed 9 days after CAR-T cell injection.To our knowledge, this is the first preclinical study demonstrating that men-i induces the immunotargetCLEC12A to overcome the limitations of CAR-based immunotherapy against AML. Combined men-i andCLEC12A-directed CAR-T cell treatment had dramatic anti-leukemic effects in vitro and in vivo and shouldsoon be available for clinical..."

CAR T-Cell Therapy • IO biomarker • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • CLEC12A • HAVCR2 • IFNG • ITGAM • KMT2A • LAG3 • MEIS1 • NPM1 • PD-1 • TIGIT

Histone methyltransferase KMT2D targets the SPOP-G3BP1 axis to enhance AR stability and drive castration-resistant prostate cancer progression. (PubMed, Mol Biomed) - "Furthermore, we explored a novel combination therapy involving the histone methyltransferase inhibitor MI-503 and enzalutamide in AR-positive and AR splice variant-positive cell lines. Our results confirmed the synergistic therapeutic effects of this combination, which can continue to inhibit the AR signaling pathway during the CRPC stage, thereby delaying disease progression. Taken together, our findings elucidate a critical KMT2D/G3BP1/SPOP/AR regulatory axis in prostate cancer progression and propose that targeted inhibition of histone methylation in combination with anti-androgen therapy represents a promising strategy for the management of advanced prostate cancer."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • G3BP1 • KMT2D • SPOP

Targeting IGF2BP3 Enhances Anti-Leukemic Effects of Menin-MLL Inhibition in MLL-AF4 Leukemia (ASH 2023) - "Our work shows that IGF2BP3 is an oncogenic amplifier of MLL-AF4 mediated leukemogenesis and is a potent therapeutic target and suggests a novel combinatorial approach to targeting leukemia at both the transcriptional and post-transcriptional level."

Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Oncology • IGF2BP3 • ITGAM • KIT

Targeting the Menin-KMT2A Chromatin Complex to Boost CAR-T Cell Therapy against NPM1 mutated and KMT2A>-rearranged AML (DGHO 2025) - "Lentivirally engineered CAR-cells targeting the identified immunotarget were evaluated in vitro for anti-leukemic potential combined with Men-i against NPM1m AML. RNAseq analysis of KMT2A-r and NPM1m AML cell lines (MV411, MOLM13, OCI-AML3) revealed that immune antigen-1 was consistently upregulated by various Men-i (MI-503, ziftomenib, revumenib). Men-i demonstrates remarkable clinical efficacy against NPM1m and KMT2A-r AML, induces a novel immunotarget on AML cells, and sensitizes these cells for CAR-based therapy without adversely affecting immune effector cell function. Confirmatory in vivo assessment of this combination is underway."

CAR T-Cell Therapy • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • HAVCR2 • KMT2A • LAG3 • MEIS1 • NPM1 • PD-1 • TIGIT

KMT2D deficiency potentiates antitumor immunity and sensitizes immune checkpoint blockade in urologic cancers. (PubMed, J Pathol) - "Finally, the small-molecule inhibitor MI-503 combined with anti-PD-1 therapy suppressed tumor growth on the PDUTF platform. Collectively, KMT2D deficiency sensitizes tumor cells to ICB, and inhibiting KMT2D may represent a promising approach in combination with ICB to improve patient prognosis."

Checkpoint inhibition • Journal • Genito-urinary Cancer • Oncology • Urethral Cancer • KMT2D

MLL1 histone methyltransferase mediates the up-regulation of NADPH oxidase expression in atherosclerotic mice (ECP 2025) - "Male ApoE-/- mice fed a standard rodent chow or an atherogenic diet were randomized to receive 5 mg/kg MI-503, a specific MLL1 pharmacological inhibitor, or vehicle, for 4 weeks... Here, we report that MLL1 plays a role in mediating the up-regulation of Nox expression, an important mechanism leading to ROS overproduction in experimental atherosclerosis. Pharmacological inhibition of MLL1 could become an additional therapeutic target to attenuate oxidant stress in atherosclerotic cardiovascular disorders."

Epigenetic controller • Preclinical • Atherosclerosis • Hematological Malignancies • Leukemia • Oncology • APOE • NOX4 • NOX5

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

Menin inhibitor MI-503 exhibits potent anti-cancer activity in osteosarcoma. (PubMed, Sci Rep) - "In a study with 143B cell-derived xenograft model, we found that MI-503 profoundly inhibited OS tumor growth in mice. Immunohistochemistry (IHC) study showed that MI-503 suppressed the H3K4 methylation and inhibited the expression of the cell proliferation biomarker Ki67 in 143B OS xenograft tissue.Overall, our findings demonstrated the potent anti-OS activity of MI-503 in both in vitro and in vivo models, which also indicated that Menin inhibitor may be a prospective therapeutic strategy for human OS."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • KMT2A • MCL1 • MYC • PARP1

Synergistic effects of the KDM4C inhibitor SD70 and the menin inhibitor MI-503 against MLL::AF9-driven acute myeloid leukaemia. (PubMed, Br J Haematol) - "Differential gene expression analysis by RNA-seq following combined pharmacological inhibition of SD70 and MI-503 revealed changes in numerous genes, with MYC target genes being the most significantly downregulated. Taken together, these data provide preclinical evidence that the combination of SD70 and MI-503 is a potential dual-targeted therapy for MLL::AF9 AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34 • KMT2A

Direct targeting of the COMPASS complex inhibits neuroblastoma growth by inhibiting cancer stem cells (AACR 2024) - "Furthermore, MI-503 in a dose-dependent manner synergistically sensitizes NB to chemotherapy doxorubicin and significantly inhibits NB proliferation and spheroid growth compared to either agent alone. Our data show that MI-503 or MEN1 knockdown leads to significant inhibition of NB growth by directly inhibiting NB CSCs in both in vitro and in vivo tumor models. Further developing these epigenetic-based therapeutic strategies and combining them with current therapies will pave the way for effectively managing NB."

Cancer stem • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • CD14 • CSF3R • MEN1

Repressing HIF-1α-induced HDAC9 contributes to the synergistic effect of venetoclax and MENIN inhibitor in KMT2Ar AML. (PubMed, Biomark Res) - "KMT2Ar-AML has been demonstrated to be sensitive to BCL2 inhibitor venetoclax (VEN), but these patients are unable to benefit from current VEN-based regimen (VEN plus azacitidine or low dose-cytarabine), so a novel and KMT2A rearrangement-specific targeting partner is required, and MENIN inhibitor (MEN1i) is a promising one. Hypoxia induction sensitized KMT2Ar-AML to VEN plus MI-503-mediated proliferation inhibition and apoptosis induction. Therefore, repressing HIF-1A-induced HDAC9 contributed to the synergistic effect of VEN and MEN1i in KMT2Ar-AML."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • BCL2L1 • HDAC9 • HIF1A • HOXA9 • KMT2A • MEIS1

Targeting IGF2BP3 enhances antileukemic effects of menin-MLL inhibition in MLL-AF4 leukemia. (PubMed, Blood Adv) - "IGF2BP3 knockdown had a greater effect on increasing survival and attenuating disease than pharmacologic menin-MLL inhibition with MI-503 alone and showed enhanced anti-leukemic effects in combination. Our work shows that IGF2BP3 is an oncogenic amplifier of MLL-AF4 mediated leukemogenesis and is a potent therapeutic target and provides a paradigm for targeting leukemia at both the transcriptional and post-transcriptional level."

Journal • Hematological Malignancies • Leukemia • Oncology • IGF2BP3

MLL1 Activation Contributes to Renal Protection and Regeneration Following AKI Induced by Folic Acid and Ischemia/Reperfusion (KIDNEY WEEK 2023) - "Collectively, these data suggest that MLL1 contributes to renal protection and functional recovery and promotes renal regeneration through a mechanism associated with activation of the EGFR signaling pathway."

Acute Kidney Injury • Cardiovascular • Hematological Malignancies • Leukemia • Nephrology • Oncology • Renal Disease • Reperfusion Injury • KIM1 • LCN2 • PCNA • STAT3 • VIM • WDR5

Cooperative role of the master transcription factor CEBPα during MLL-ENL-mediated leukemic transformation of human CD34+ progenitors (DGHO 2023) - "A combination of the MLL inhibitor MI-503 and OICR-9429 induced strong anti-proliferative effects, superior to single agent treatment. Taken together, our human primary MLL-ENL monocytic AML model allows precise studies about oncogenic mechanisms and drug testing ex vivo . The strong cooperativity of MLL-ENL and CEBPα during leukemic transformation defines CEBPα and its downstream pathways attractive targets to inhibit aggressive human MLL-r leukemia."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CCR2 • CD34 • CEBPA • CXCR4 • FASN • FLT3

Pharmacological inhibition of the MLL1-menin-interaction aggravates acute kidney injury induced by folic acid and ischemia/reperfusion in mice. (PubMed, Am J Physiol Renal Physiol) - "Moreover, MI503 inhibited FA-induced phosphorylation of epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 and extracellular signal-regulated kinase-1/2 in injured kidneys. Collectively, these data suggest that MLL1 contributes to renal protection and functional recovery and promotes renal regeneration through a mechanism associated with activation of the EGFR signaling pathway."

Journal • Preclinical • Acute Kidney Injury • Cardiovascular • Hematological Malignancies • Leukemia • Nephrology • Oncology • Renal Disease • Reperfusion Injury • KIM1 • LCN2 • PCNA • STAT3 • VIM • WDR5

Clinically Defined Mutations in MEN1 Alter Its Tumor-suppressive Function Through Increased Menin Turnover. (PubMed, Cancer Res Commun) - "We report that these mutations and variant promote tumor cell growth and gastrin expression by rendering menin protein unstable and prone to increased degradation. We demonstrate that the menin-MLL (mixed lineage leukemia) inhibitor MI-503 restores menin protein expression and function in vitro and in vivo, suggesting a potential novel therapeutic approach to target MEN1 GEP-NETs."

Journal • Endocrine Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Hematological Malignancies • Leukemia • Neuroendocrine Tumor • Oncology • Solid Tumor • GAST • MEN1

Epigenetic regulator Menin-MLL1 maintains cancer stem cells and promotes neuroblastoma growth (AACR 2023) - "In our future efforts, we will develop concomitant therapeutic approaches by combining MI-503 with current chemotherapies to target both NB CSCs and bulk tumor cells. This will lead to the development of effective, targeted, and clinically tractable therapies for NB patients."

Cancer stem • Late-breaking abstract • CNS Tumor • Hematological Malignancies • Leukemia • Neuroblastoma • Neuroendocrine Tumor • Oncology • Solid Tumor • CD14 • CSF3R • MEIS1 • MYCN • NANOG • POU5F1

Epigenetic Regulation as a New Therapeutic Target for Middle Ear Cholesteatoma. (PubMed, Otol Neurotol) - "These findings demonstrate an encouraging safety profile for the use of menin-MLL inhibitor for the conservative treatment of cholesteatoma."

Journal • Otorhinolaryngology

Inhibition of MLL1-menin interaction attenuates renal fibrosis in obstructive nephropathy. (PubMed, FASEB J) - "Finally, MI-503 was effective in abrogating serum or TGFβ1-induced transformation of renal interstitial fibroblasts to myofibroblasts in vitro. Taken together, these results suggest that targeting disruption of the MLL1-menin interaction attenuates renal fibrosis through inhibition of partial EMT and renal fibroblast activation."

Journal • Fibrosis • Hematological Malignancies • Immunology • Leukemia • Oncology • Renal Disease • CDH1 • FN1 • SMAD3 • TGFB1

Pharmacologic Inhibition of DYRK1A Results in Hyperactivation and Hyperphosphorylation of MYC and ERK Rendering KMT2A-R ALL Cells Sensitive to BCL2 Inhibition (ASH 2022) - " In vitro treatment studies using three different menin inhibitors (MI-2-2 / MI-503 / VTP50469) to disrupt the transcriptional activity of the KMT2A-R complex resulted in the downregulation of DYRK1A at the RNA and the protein level...Supporting our hypothesis, combining DYRK1A inhibitors with the MEK inhibitor trametinib antagonistically rescued KMT2A-R ALL cell proliferation, indicating that ERK hyperactivation is the main driver of DYRK1A inhibitor mediated cell cycle arrest... Our results validate DYRK1A as an important molecule to regulate cell proliferation via inhibition of MYC and ERK. Targeting DYRK1A results in the accumulation of BIM, which renders the cells sensitive to BCL2 inhibition via venetoclax. While further in vivo studies are needed, we predict that combining DYRK1A inhibition with venetoclax may be a novel precision medicine strategy for the treatment of KMT2A-R ALL."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Burkitt Lymphoma • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Oncology • KMT2A

Wychimicins, a new class of spirotetronate polyketides from Actinocrispum wychmicini MI503-A4. (PubMed, J Antibiot (Tokyo)) - "In X-ray crystal structure analysis, the Flack constant was 0.10 (11). The stereochemistry of the spirocarbon C-25 was R. Wychimicins had a minimum inhibitory concentration of 0.125-2 µg ml against methicillin-resistant Staphylococcus aureus."

Journal • Infectious Disease

Menin inhibitors as targeted therapeutics in KMT2a rearranged infant leukemia and the identification of effective treatment combinations. (ASCO 2022) - "Within the panel of menin inhibitors, infant B-ALL cells were found to be more sensitive to MI-463, MI-503 and MI-136 with a mean IC50 of 5.9µM, 6.1µM and 10.2µM, respectively...For example, carfilzomib synergised with menin inhibitors over a broad range of concentrations with a CI value of 0.7. In this study, we present and discuss the initial proof-of-concept preclinical data for the effective anti-leukemic activity of menin inhibition against KMT2A-rearranged infant leukemia cells. Furthermore, the comprehensive drug screen and drug combination studies identified a spectrum of mechanistically-validated synergies, providing usable data for the formulation of multi-agent clinical studies for this currently unmet need in pediatric oncology."

Hematological Malignancies • Leukemia • Oncology • Pediatrics • KMT2A

Direct targeting of epigenetic regulator Menin inhibits neuroblastoma growth. (PubMed, FASEB J) - "Inhibition of menin-MLL1 interaction by a specific small-molecule inhibitor MI-503 leads to the inhibition of epigenetic regulator functions and inhibits NB growth. Our future efforts will focus on further elucidating the role of menin in NB and to develop effective therapeutic strategies incorporating epigenetic inhibitors for NB patients."

Journal • Immunology • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • MEIS1 • MYCN

Inhibition of epigenetic regulator menin is a novel therapeutic approach for high-risk neuroblastoma (AACR 2022) - "In our future efforts, we will further elucidate the effects of MI-503 and the role of Menin in NB by using in vivo tumor models. Epigenetic inhibitor such as MI-503 holds significant potential for further clinical development and as a novel therapeutic approach for NB."

Neuroblastoma • Oncology • Solid Tumor • KMT2A • MYCN