ArticleCancer cell international2023
A novel Menin-MLL1 inhibitor, DS-1594a, prevents the progression of acute leukemia with rearranged MLL1 or mutated NPM1.
Article in Cancer cell international, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04752163 (An Open-Label Phase 1/2 Multi-Arm Study of DS-1594b as a Single-Agent and in Combination With Azacitidine and Venetoclax or Mini-HCVD for the Treatment of Patients With Acute Myeloid Leukemia), which is not on this map. Cited by 21 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
An Open-Label Phase 1/2 Multi-Arm Study of DS-1594b as a Single-Agent and in Combination With Azacitidine and Venetoclax or Mini-HCVD for the Treatment of Patients With Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL)
Who cites it
21 citing papers in PubMed, 26 citations in OpenAlex.
- A phase 1/2 study of DS-1594 menin inhibitor in relapsed/refractory acute leukemias.Journal of hematology & oncology · 2025Trial
- Review
- Menin inhibitors as a treatment for acute leukemia: from bench to the clinic.Blood neoplasia · 2026Review
- Menin Inhibition in Acute Myeloid Leukemia: Rewiring Leukemic Transcriptional Networks.International journal of molecular sciences · 2026Review
- CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials.Nature communications · 2026Article
- Article
- Methylome profiling reveals context-dependent chemo-resistance mechanisms and enhances risk stratification in AML.Cancer cell international · 2026Article
- Current perspectives on KMT2A fusion proteins and menin inhibition in paediatric acute myeloid leukaemia.The FEBS journal · 2026Review
- Management of Acute Myeloid Leukemia: A Review.Cancers · 2026Review
- Identification of novel Menin-MLL interaction inhibitors targeting leukemia using in-silico virtual screening and structure-based drug design approaches.Journal, genetic engineering & biotechnology · 2025Article
- Therapeutic Implications of Menin Inhibitors in the Treatment of Acute Leukemia: A Critical Review.Diseases (Basel, Switzerland) · 2025Review
- Review
- Insights into KMT2A rearrangements in acute myeloid leukemia: from molecular characteristics to targeted therapies.Biomarker research · 2025Review
- Menin: from molecular insights to clinical impact.Epigenomics · 2025Review
- Long noncoding RNAs in acute myeloid leukemia: biomarkers, prognostic indicators, and treatment potential.Cancer cell international · 2025Review
- Targeting menin for precision therapy in high-risk acute myeloid leukemia.Leukemia research reports · 2025Review
- Article
- Menin inhibitors for the treatment of acute myeloid leukemia: challenges and opportunities ahead.Journal of hematology & oncology · 2024Review
- Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition inInternational journal of molecular sciences · 2024Article
- A 2024 Update on Menin Inhibitors. A New Class of Target Agents against KMT2A-Rearranged and NPM1-Mutated Acute Myeloid Leukemia.Hematology reports · 2024Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
37 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMixed lineage leukemia 1-rearranged (MLL1-r) acute leukemia patients respond poorly to currently available treatments and there is a need to develop more effective therapies directly disrupting the Menin‒MLL1 complex. Small-molecule-mediated inhibition of the protein‒protein interaction between Menin and MLL1 fusion proteins is a potential therapeutic strategy for patients with MLL1-r or mutated-nucleophosmin 1 (NPM1c) acute leukemia. In this study, we preclinically evaluated the new compound DS-1594a and its salts.
methodsWe evaluated the preclinical efficacy of DS-1594a as well as DS-1594a·HCl (the HCl salt of DS-1594a) and DS-1594a·succinate (the succinic acid salt of DS-1594a, DS-1594b) in vitro and in vivo using acute myeloid leukemia (AML)/acute lymphoblastic leukemia (ALL) models.
resultsOur results showed that MLL1-r or NPM1c human leukemic cell lines were selectively and highly sensitive to DS-1594a·HCl, with 50% growth inhibition values < 30 nM. Compared with cytrabine, the standard chemotherapy drug as AML therapy, both DS-1594a·HCl and DS-1594a·succinate mediated the eradication of potential leukemia-initiating cells by enhancing differentiation and reducing serial colony-forming potential in MLL1-r AML cells in vitro. The results were confirmed by flow cytometry, RNA sequencing, RT‒qPCR and chromatin immunoprecipitation sequencing analyses. DS-1594a·HCl and DS-1594a·succinate exhibited significant antitumor efficacy and survival benefit in MOLM-13 cell and patient-derived xenograft models of MLL1-r or NPM1c acute leukemia in vivo.
conclusionWe have generated a novel, potent, orally available small-molecule inhibitor of the Menin-MLL1 interaction, DS-1594a. Our results suggest that DS-1594a has medicinal properties distinct from those of cytarabine and that DS-1594a has the potential to be a new anticancer therapy and support oral dosing regimen for clinical studies (NCT04752163).
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.