VTP-50469 / Syndax Pharma, AbbVie - LARVOL DELTA

Co-targeting menin and RAS in KMT2A-r/NPM1c AML with activated RTK//RAS/MAPK signaling (ASH 2025) - "The combination of SNDX-50469 and RM-028 synergisticallyinduced cell death not only in parental but also in SNDX-R OCI-AML3 cells.To understand the potential mechanisms of synergistic effects, we treated MOLM-13 cells withRM-028, SDNX-50469, and both and then performed reversed-phase protein arrays which detect>400 proteins. RAS and/or RAS/menin inhibition targets multiple signaling pathways thatsupport protein synthesis, cell proliferation, and survival. The combination is more effective indecreasing antiapoptotic proteins, increasing proapoptotic proteins and DNA damage responses,and activating caspases.Collectively, we demonstrate that co-targeting menin and RAS inhibits HOX/MEIS and RASsignaling, more effectively decreases antiapoptotic/increases proapoptotic proteins, andsynergistically induces cell death in KMT2A-r/NPM1c AML with activated RTK//RAS/MAPKsignaling, with the potential of enhancing venetoclax activity."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • BCL2 • FLT3 • GLI2 • KMT2A • KRAS • MCL1 • MEIS1 • NF1 • NPM1 • NRAS • NUP98 • PTPN11

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

Combining Menin and MEK Inhibition to Target Poor Prognostic KMT2A-Rearranged RAS Pathway-Mutant Acute Leukemia (ASH 2023) - "We evaluated the combination of RAS/MAPK targeting using the MEK1/2 inhibitor selumetinib with VTP-50469, a close analog of revumenib, in pediatric leukemias harboring both KMT2A-r and RAS mutations. The findings in our preclinical study suggest a promising, readily translatable targeted treatment for this patient population. Mechanistically, enhanced downregulation of both MYC signaling and the RAS/MAPK pathway with the combinatorial therapy is likely a strong contributor to the observed efficacy."

Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • KMT2A • KRAS • MEIS1 • MEN1 • NRAS • PTPN11

Menin inhibition impairs metastatic colonization of Ewing sarcoma. (PubMed, bioRxiv) - "Exposing EwS cells to the Menin inhibitor VTP50469 (revumenib) inhibited expression of MYC targets and co-immunoprecipitation studies detected Menin:MYC interactions that were partially disrupted by the drug. Metastatic colonization of disseminated EwS cells in vivo was significantly inhibited in mice fed VTP50469 chow. Together these findings implicate Menin as a mediator of EwS metastasis and suggest that Menin inhibitors warrant investigation as novel therapeutics for patients with high-risk disease."

Journal • Ewing Sarcoma • Hematological Malignancies • Leukemia • Oncology • Sarcoma • Solid Tumor • MYC

Decoding the Epigenetic Drivers of Menin-MLL Inhibitor Resistance in KMT2A-Rearranged Acute Myeloid Leukemia (ASH 2023) - "Consistent with our screen results, the depletion of PRC1.1 components led to a markedly increase in IC50 values when treated with the Menin inhibitor VTP50469 in both human and murine KMT2A-rearranged cell models...This is consistent with recent data from phase I clinical trial of revumenib (SNDX-5613) and preclinical patient derived xenograft models, wherein the Menin inhibitor persistently inhibited key KMT2A targets, even in resistant samples...In summary, our study identifies the non-canonical PRC1.1 as a key epigenetic driver of Menin-MLL resistance through a KMT2A target gene-independent mechanism which involves aberrant activation of MYC. We have further provided evidence that AML cells with loss of PRC1.1 are hypersensitive to BCL-2 inhibitor Venetoclax, opening a new therapeutic avenue for tackling Menin-resistant AMLs driven by polycomb inactivation."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCOR • KMT2A • MEF2C • MEIS1 • MYC • NPM1 • PBX3 • SUZ12

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

Synergistic Efficacy of Dual Menin and PRMT5 Targeting Against NPM1 mutated and KMT2A-rearranged Leukemia (ASH 2024) - "First, we assessed the PRMT5-i JNJ-64619178 (JNJ) and GSK3326595 (GSK) as single drugs...There was significant drug synergy of both PRMT5-i with each of two novel Men-i VTP50469 (VTP) and KO-539, while we found only moderate growth inhibition and no synergy in HL60 cells (wildtype for KMT2A and NPM1) that served as negative control...Four weeks of in vivo treatment significantly reduced leukemia burden in peripheral blood and bone marrow and significantly enhanced mice survival compared to single drugs and vehicle control. The presented data underscore the therapeutic potential of combined Menin and PRMT5 inhibition as a novel synergistic approach to targeting NPM1mut and KMT2A-r leukemias and is already available for clinical investigation."

Clinical • Hematological Malignancies • Leukemia • Oncology • ANXA5 • ITGAM • JAK2 • KMT2A • MEIS1 • MEN1 • NPM1 • PBX3 • PRMT5

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

Menin inhibition impairs metastatic colonization of Ewing sarcoma (AACR 2025) - "In MLL rearranged (MLLr) leukemia, menin functions as an oncogene and a small molecule inhibitor of menin was recently FDA approved for MLLr leukemia therapy (Revumenib, Syndax). Histology studies of VTP50469 mice are pending and will be presented at the meeting. These data reveal a critical role for menin in EwS tumor colonization and suggest that menin inhibitors could be repurposed as metastasis prevention agents in EwS patients who are at high risk of metastatic relapse."

Late-breaking abstract • Metastases • Colorectal Cancer • Ewing Sarcoma • Hematological Malignancies • Leukemia • Oncology • Sarcoma • Solid Tumor • MYC • TGFB1

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

Arachidonic acid released by PIK3CA mutant tumor cells triggers malignant transformation of colonic epithelium by inducing chromatin remodeling. (PubMed, Cell Rep Med) - "Finally, the combination of VTP50469, an inhibitor of the Menin-MLL interaction, and alpelisib synergistically represses PDX tumors harboring PIK3CA mutations. Together, these findings unveil the metabolic link between PIK3CA mutant tumor cells and the IECs, highlighting AA as the potential target for the treatment of patients with CRC harboring PIK3CA mutations."

Journal • Tumor cell • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • FBXW7 • PIK3CA

Menin drives oncogenesis in Ewing sarcoma cells by activating transcription of key metastatic factors (AACR 2024) - "To determine if genes altered in MEN1-KO cells were dependent on the role of Menin in Menin/MLL methyltransferase complexes, we analyzed transcriptomes of EwS cells that had been exposed to the Menin/MLL interaction inhibitor, VTP-50469...Finally, we found that Menin and EWS::FLI1 co-immunoprecipitate in EwS nuclear extracts suggesting that they may exist in complex with one another at sites of shared gene regulation. Taken together, these data indicate that Menin promotes EwS metastasis and that this is achieved by its function as a scaffolding protein that augments the transcriptional activity of EWS::FLI1 at intragenic enhancers of pro-metastasis genes."

Metastases • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • CAV1 • FLI1 • IL1RAP • MEN1 • MYC • STEAP1

Mezigdomide is effective alone and in combination with Menin inhibition in pre-clinical models of KMT2A-r and NPM1c AML. (PubMed, Blood) - "We have previously identified IKZF1/IKAROS as a target in KMT2A-r AML and shown in preclinical models that IKAROS protein degradation with lenalidomide or iberdomide has modest single-agent activity yet can synergize with Menin inhibitors. The combination of mezigdomide with the Menin inhibitor VTP-50469 increased survival and prevented and overcame MEN1 mutations that mediate resistance in patients receiving Menin inhibitor monotherapy. These results support prioritization of mezigdomide for early phase clinical trials in KMT2A-r and NPM1c AML, either as a single-agent or in combination with Menin inhibitors."

Combination therapy • Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • IKZF1 • KMT2A • MEN1 • NPM1

The menin inhibitor VTP-50469 enhances the in vivo efficacy of established drugs against preclinical models of aggressive infant MLL-r acute lymphoblastic leukemia. (AACR-NCI-EORTC 2023) - No abstract available

Preclinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

COMBINING MENIN AND MEK INHIBITION TO TREAT CHILDREN WITH POOR PROGNOSTIC KMT2A-R RAS-MUTANT ACUTE LEUKEMIA (EHA 2023) - "We evaluated the combination of RAS/MAPK pathway inhibition by the MEK1/2 inhibitor selumetinib with the Menin inhibitor VTP-50469 (SNDX-5613) in a genetically defined, poor prognostic subgroup of pediatric leukemia harboring KMT2A-r with RAS mutations. The findings in our preclinical study suggest a promising, readily translatable treatment for patients with KMT2A-racute leukemias harboring RAS mutations. Mechanistically, enhanced downregulation of both MYC signaling and the RAS/MAPK pathway with the combinatorial therapy is likely a strong contributor to the observed efficacy. MYC, Acute leukemia, KMT2A"

Clinical • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • KMT2A • MEIS1 • PTPRC

NON-GENETIC RESISTANCE TO MENIN INHIBITION IN AML IS REVERSIBLE BY PERTURBATION OF KAT6A (EHA 2023) - "To generate a cell line system that would allow to study the underlying mechanistic principles with more granularity, we transplanted OCI-AML2 cells into immunodeficient mice and treated them with the Menin- inhibitor VTP-50469 followed by harvest of resistant cells from relapsed animals... We were able to establish the phenomenon of non-genetic cellular adaptation as a mechanism of resistance towards Menin-MLL1 inhibition in MLL-rearranged leukemia. Importantly, we provided preclinical proof-of- principle that such a reprogrammed cell state is reversible by pharmacologic targeting of a critical epigenetic switch. Resistance, MLL, AML, Epigenetic"

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • KAT6A • MEIS1 • MEN1 • NPM1

Mutant NPM1 Is Recruited to MLL Target Genes Via Its Acidic Stretch and Nuclear Export Factor CRM1 and Regulates Oncogenic Transcription in Acute Myeloid Leukemia (ASH 2022) - "In addition, we demonstrated that NPM1c and CRM1 are lost from a subset of NPM1c target loci after treatment with the small molecule Menin-MLL interaction inhibitor VTP-50469, which can be enhanced by the addition of CRM1 inhibitor Selinexor. Overall, we demonstrate that NPM1c chromatin binding is mediated by a combination of factors, including the CRM1-NES interaction, the acidic region of NPM1c, and the presence of the MLL complex. We further show that NPM1c acts in collaboration with the MLL1 complex to enhance oncogenic transcription and define the mechanism by which MLL1-Menin small molecule inhibitors produce clinical responses in patients with NPM1-mutated AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • HOXA9 • MEIS1 • NPM1

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

Epigenetic Resistance to Menin-MLL1 Inhibition Is Driven By Loss of the Non-Canonical Polycomb Repressive Complex 1.1 in NUP98-Rearranged AML (ASH 2022) - "Menin-MLL1 inhibition using a small molecule VTP50469 simultaneously represses pro-leukemogenic genes and upregulates markers of myeloid differentiation...In summary, these results demonstrate that the NUP98-fusion-Menin-MLL complex and PRC1.1 dynamically compete for transcriptional control of developmentally regulated, stem-cell associated genes. Loss of PRC1.1 may promote NUP98-fusion protein-driven leukemogenesis and mediates resistance to Menin-MLL1 inhibition by failing to epigenetically silence genes that are essential for maintaining an undifferentiated, stem cell-like state."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • MEIS1 • NUP98 • PBX3

The Menin-MLL1 Interaction Is a Molecular Dependency in NUP98-Rearranged AML (ASH 2021) - "Using mouse leukemia cell lines driven by NUP98-HOXA9 and NUP98-JARID1A fusion oncoproteins, we demonstrate that NUP98-fusion driven leukemia is sensitive to the Menin-MLL1 inhibitor VTP50469, with an IC50 similar to what we have previously reported for MLL -rearranged and NPM1c leukemia cells...Gene expression analysis revealed that Menin-MLL1 inhibition simultaneously suppresses a pro-leukemogenic gene expression program, including downregulation of the HOXA cluster, and upregulates tissue-specific markers of differentiation. These preclinical results suggest that Menin-MLL1 inhibition may represent a rational, targeted therapy for patients with NUP98 -rearranged leukemias."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ARID1A • HOXA9 • ITGAM • KDM5A • MEIS1 • NSD1 • NUP98

Potent Ikaros Degradation By the Cereblon E3 Ligase Modulator CC-92480 Is Effective in Combination with Menin-MLL1 Inhibition in MLL1-Rearranged and NPM1-Mutant AML (ASH 2021) - "Lenalidomide, CC-220, and CC-92480 all synergized with VTP-50469 to inhibit proliferation. In two of these experiments CC-92480 was also compared to lenalidomide and increased survival by 23.4% (p < 0.0005) and 28.1% (p < 0.05). In summary, the preclinical activity of CC-92480 in MLL1 -r and NPM1c AML models, particularly in combination with Menin-MLL1 inhibition, supports translation of this compound or a similarly potent, Ikaros-degrading CELMoD into clinical trials for these molecular subtypes of AML."

Combination therapy • Acute Myelogenous Leukemia • Hematological Malignancies • Immune Modulation • Inflammation • Leukemia • Multiple Myeloma • Oncology • Targeted Protein Degradation • CRBN • HOXA9 • IKZF1 • KMT2A • MEIS1 • NPM1

The Menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML. (PubMed, Blood) - "Using mouse leukemia cell lines driven by NUP98-HOXA9 and NUP98-JARID1A fusion oncoproteins, we demonstrate that NUP98-fusion driven leukemia is sensitive to the Menin-MLL1 inhibitor VTP50469, with an IC50 similar to what we have previously reported for MLL-rearranged and NPM1c leukemia cells...Gene expression analysis revealed that Menin-MLL1 inhibition simultaneously suppresses a pro-leukemogenic gene expression program, including downregulation of the HOXA cluster, and upregulates tissue-specific markers of differentiation. These preclinical results suggest that Menin-MLL1 inhibition may represent a rational, targeted therapy for patients with NUP98-rearranged leukemias."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ARID1A • HOXA9 • ITGAM • MEIS1 • NSD1 • NUP98

[VIRTUAL] Menin Inhibition Decreases Bcl-2 and Bcl-xL and Enhances Venetoclax Activity in NPM1/FLT3-Mutated AML (SOHO 2021) - "Objective: Investigate anti-leukemic activities, potential synergism, and mechanisms of menin-MLL1 inhibitor SDNX-50469, an equipotent surrogate of the clinical compound SNDX-5613 and venetoclax combination in vivo in an NPM1c/ FLT3-ITD/TKD PDX model. Our study validated menin as a therapeutic target and demonstrated that its inhibition synergizes with venetoclax in NPM1/FLT3-mutated AML, which warrants clinical evaluation. Inhibition of FLT3 may further enhance menin and Bcl-2 co-targeting efficacy in NPM1- and FLT3-mutated AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • CD34 • CD38 • FLT3 • ITGAM • NPM1 • PTPRC

[VIRTUAL] MENIN INHIBITION DECREASES BCL-2 AND SYNERGIZES WITH VENETOCLAX IN NPM1/FLT3-MUTATED AML (EHA 2021) - "Aims To investigate the anti-leukemic activity and potential synergism and mechanisms of the combination of the menin-MLL1 inhibitor SDNX-50469, an equipotent surrogate of the clinical compound SNDX-5613 and venetoclax in vivo in an NPM1c/FLT3-ITD/TKD patient-derived xenograft (PDX) model. Conclusion Our study further validated menin as a therapeutic target and demonstrated that its inhibition synergizes with venetoclax in NPM1/FLT3-mutated AML, which warrants further clinical evaluation. Inhibition of FLT3 may further enhance the therapeutic efficacy of menin and Bcl-2 co-targeting in NPM1 and FLT3 mutated AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • CD34 • CD38 • FLT3 • ITGAM • NPM1 • PTPRC

Evaluation of VTP-50469, a menin-MLL1 inhibitor, against Ewing sarcoma xenograft models by the pediatric preclinical testing consortium. (PubMed, Pediatr Blood Cancer) - "In contrast to its high level of activity against MLL1-rearranged leukemia xenografts, VTP-50469 shows little activity against EwS models."

Journal • Ewing Sarcoma • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Sarcoma