Menin-MLL Inhibitor Pipeline in AML — PatSnap Eureka
Menin-MLL Inhibitor Pipeline in NPM1-Mutant AML & MLL-Rearranged Leukemia
Two molecularly distinct leukemia subtypes share a common epigenetic vulnerability in the menin-MLL protein–protein interaction. Thienopyrimidine-class inhibitors have entered Phase I/II trials — here is the complete IP, clinical, and resistance landscape from patent and literature analysis.
Two Distinct Leukemia Subtypes, One Shared Epigenetic Vulnerability
NPM1 mutation is the most common genetic alteration in acute myeloid leukemia, detected in about 30–35% of adult AML and more than 50% of AML with normal karyotype. The mutant nucleophosmin protein undergoes cytoplasmic dislocation — a hallmark feature — and re-wires HOX gene expression through MLL1-menin. Research from the University of Perugia (2022) establishes NPM1 mutation status as a stable biomarker detectable by standard molecular diagnostics.
The MLL-rearranged (MLL-r) subtype involves over 80 documented fusion partner genes, with the majority of leukemias arising from approximately six common partners: MLL-AF4/AFF1, MLL-AF9/MLLT3, MLL-ENL, MLL-AF10, MLL-AF6, and MLL-ELL. MLL-r leukemia accounts for approximately 75% of infant and approximately 10% of adult acute leukemia cases.
In both subtypes, the menin protein — encoded by the MEN1 tumor suppressor gene — acts as an obligate oncogenic cofactor. Menin binds directly to MLL1 fusion proteins and to wild-type MLL1 in NPM1-mutant cells, tethering the complex to HOXA cluster and MEIS1 loci to maintain a leukemia-sustaining transcriptional program. Downstream oncogenic targets activated by the menin-MLL complex include HOXA9, MEIS1, MYC, and BCL2 — all downregulated upon pharmacological menin-MLL disruption. This mechanistic convergence is the foundation for the life sciences IP intelligence approach PatSnap Eureka applies to track this pipeline.
Memorial Sloan Kettering Cancer Center (MSK) identified the menin binding site of MLL via CRISPR-Cas9 negative selection screening as the top vulnerability in NPM1-mutant AML cells, establishing NPM1 mutation as a companion diagnostic biomarker for patient selection in menin inhibitor programs.
Four Epigenetic Strategies Targeting the MLL Complex
The retrieved dataset spans small-molecule PPI inhibitors, methyltransferase inhibitors, and demethylase inhibitors — at stages from preclinical to Phase I/II clinical trials.
Menin-MLL PPI Inhibitors (Thienopyrimidines)
The dominant modality in the dataset. Thienopyrimidine-class compounds occupy the MLL-binding cleft on the menin surface, sterically preventing formation of the oncogenic menin-MLL1 or menin-MLL-fusion complex on chromatin. These agents eradicate leukemia in xenograft models of primary MLL-rearranged or NPM1-mutant cells and are well tolerated with few or no side effects. The earliest scaffold class includes hydroxy- and aminomethylpiperidine compounds (benchmark: MIV-6R, IC50 = 56 nM), developed via HTS of ~288,000 small molecules at Vanderbilt University. Vitae Pharmaceuticals holds an active EP patent (2023) on menin-MLL inhibitor compounds.
Phase I/II Clinical TrialsDOT1L Inhibitors (H3K79 Methyltransferase)
DOT1L, the sole H3K79 methyltransferase, maintains leukemogenic gene expression via H3K79me2/3 at HOXA9 and MEIS1. Pinometostat (EPZ-5676) is the most referenced compound, evaluated in a Phase Ib/II clinical trial in MLL-r patients. Retrieved sources note poor pharmacological properties and modest clinical effects as a monotherapy. DOT1L inhibition reduced HOXA9 and MEIS1 expression by more than 50% in MLL-r cell lines. Non-canonical DOT1L pathways additionally implicate FLT3 downregulation as a major cytotoxicity mechanism. The MSK patent portfolio explicitly claims combination of menin-MLL inhibition with DOT1L inhibition.
Phase Ib/II (pinometostat); Preclinical (new scaffolds)LSD1 (KDM1A) Inhibitors
LSD1 demethylates H3K4, opposing MLL1 methyltransferase activity. Potent LSD1 inhibitors (biochemical IC50 9.8–77 nM) strongly inhibit MLL-r leukemia cell proliferation (EC50 10–320 nM) with selectivity over other tumor types. Mechanism involves increased H3K4 methylation, downregulation of leukemia-relevant genes, induction of apoptosis, and differentiation. Research from Baylor College of Medicine demonstrates selectivity for MLL-r leukemia over other tumor types at these concentrations.
Preclinical to Early ClinicalWDR5-MLL1 Interaction Inhibitors
An alternative strategy targets the WDR5-MLL1 interaction required for complex assembly and H3K4 methyltransferase activity. MM-401 selectively blocked MLL-cell proliferation via cell-cycle arrest, apoptosis, and myeloid differentiation without toxicity to normal bone marrow cells (University of Michigan, 2014). A structurally distinct WDR5-MLL antagonist with Kd = 450 nM was reported from the Structural Genomics Consortium, inhibiting MLL core complex catalytic activity in vitro. This modality remains at preclinical stage.
PreclinicalPatent Activity, Development Stages & Combination Strategies
Visualising the key quantitative signals from patent and literature analysis via PatSnap Eureka across the menin-MLL inhibitor pipeline.
Therapeutic Modalities by Development Stage
Thienopyrimidine menin-MLL inhibitors lead the clinical race at Phase I/II; DOT1L inhibitors have Phase Ib/II data; LSD1 and WDR5 inhibitors remain preclinical-to-early-clinical.
MSK Menin-MLL Patent Portfolio by Jurisdiction
Memorial Sloan Kettering holds at least 9 filings across 5 jurisdictions, with prosecution activity spanning 2017–2026, representing the dominant single-assignee IP position in this field.
Combination Strategies in the Menin Inhibitor Pipeline
Four mechanistically rationalized combination approaches are documented in the retrieved dataset, spanning patent claims and preclinical/clinical research.
Menin Inhibitor Resistance: Genetic vs Non-Genetic
Two mechanistically distinct resistance categories have been characterised: genetic (UTX/KDM6A loss) and non-genetic (KAT6A-mediated epigenetic reprogramming), each requiring a distinct combination rescue strategy.
Who Holds the IP in Menin-MLL Inhibition?
Patent-driven innovation is concentrated in MSK and Vitae Pharmaceuticals; mechanistic research spans leading US and European academic institutions. No Asian pharmaceutical company holds a prominent position in the menin-MLL-specific subset of retrieved results.
| Assignee / Institution | Role in Dataset | Key Contribution | Jurisdictions / Status |
|---|---|---|---|
| Memorial Sloan Kettering Cancer Center | Dominant Patent Holder | 9+ filings: methods of treating NPM1-mutant & MLL-r leukemia with menin-MLL inhibitors ± DOT1L inhibition; CRISPR screen identifying menin binding site as top vulnerability; NPM1 companion diagnostic claims | US (granted 2019, 2020; pending 2026), WO (2017), EP (active 2018), CA (pending 2017), AU (active 2018, 2022, 2024) |
| Vitae Pharmaceuticals, Inc. | Compound IP Holder | Active EP patent (2023) directed to small-molecule menin-MLL inhibitor compounds — composition-of-matter claims orthogonal to MSK's method-of-treatment claims | EP (active, 2023) |
| The Rockefeller University | Academic Research | MLL1-Menin/UTX molecular switch mechanism; CDK4/6 inhibitor combination for resistance rescue; UTX as primary response determinant | Literature (2022) |
| Dana-Farber Cancer Institute / Boston Children's Hospital | Academic Research | CRISPR resistance screens; molecular switch between MLL complexes dictating menin inhibitor response | Literature (2021) |
| Baylor College of Medicine | Academic Research | LSD1 inhibitor pharmacology in MLL-r leukemia (IC50 9.8–77 nM); DOT1L inhibition sensitizing MLL-r AML to chemotherapy | Literature (2014, 2016) |
| Vanderbilt University (MLPCN) | Academic Research | First reported high-affinity menin-MLL PPI inhibitors via HTS of ~288,000 compounds; benchmark compound MIV-6R (IC50 = 56 nM) | Literature (2014) |
| Bayer AG | Commercial Research | Functional diversity of inhibitors tackling differentiation blockage in MLL-r leukemia — signals commercial interest beyond US academic-IP nexus | Literature (2019) |
Monitor Freedom-to-Operate Risks from MSK's Method-of-Treatment Claims
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What the IP & Clinical Data Mean for Drug Developers
Five strategic signals from the retrieved patent and literature dataset with direct implications for clinical programs in NPM1-mutant AML and MLL-rearranged leukemia.
IP Consolidation Risk from MSK Portfolio
MSK holds a multi-jurisdictional portfolio (US, WO, CA, EP, AU; active and pending filings 2017–2026) on methods of treating NPM1-mutant and MLL-r leukemia using menin-MLL inhibitors and combinations with DOT1L inhibitors. Competitors must closely monitor the scope of MSK's method-of-treatment claims, which could represent freedom-to-operate constraints for clinical-stage programs in these specific patient populations.
Two-Layer IP Opportunity: Compound + Method Claims
Vitae Pharmaceuticals' compound-specific EP patent (active, 2023) and MSK's method-of-treatment patents represent non-overlapping IP layers. Drug developers may need to navigate both layers — particularly if licensing thienopyrimidine scaffold IP separately from therapeutic use claims. This creates a potential licensing or partnership opportunity for programs seeking both layers of protection.
NPM1 Mutation as a Precision Medicine Biomarker
Multiple retrieved sources support NPM1 mutation status — detectable by standard molecular diagnostics — as a robust, stable biomarker for menin inhibitor sensitivity. High stability at relapse makes it a clinically actionable precision medicine framework for enriched trial enrollment and potentially for regulatory submissions in a molecularly defined indication. MSK patents explicitly describe NPM1 mutation testing as a companion diagnostic approach.
From Preclinical Efficacy to Remarkable Clinical Results
The most direct clinical efficacy signal in the dataset comes from an MSK conference abstract (2023) describing "remarkable efficacy in clinical trials in relapsed and therapy refractory MLL-rearranged and NPM1 mutant AML," with menin inhibition producing "profound epigenetic reprogramming of leukemia cells resulting in terminal myeloid differentiation."
The University of Freiburg/DKFZ review (2021) explicitly states that thienopyrimidine-class menin-MLL inhibitors "have recently entered phase I/II clinical trials for treating acute leukemias characterized by MLL/KMT2A translocations or NPM1 mutations." The University of Pennsylvania review (2022) similarly confirms clinical trial activity for menin inhibitors in KMT2A-rearranged and NPM1-mutant subgroups. For current trial registrations, ClinicalTrials.gov provides the authoritative registry.
DOT1L inhibitor pinometostat was evaluated in a clinical trial recruiting pediatric MLL-r leukemic patients, with modest clinical effects observed. The MSK 2023 abstract also describes use of primary patient material, PDX models, and AML cell lines for resistance characterization — indicating IND-enabling translational infrastructure is in place.
Separately, Stanford University researchers identified two endogenous NPM1-mutation-bearing HLA Class I ligands in primary patient samples with predicted binding to common HLA haplotypes HLA-A*03:01 and HLA-A*02:01, signaling parallel immunotherapy development opportunities in this patient population. PatSnap's life sciences intelligence platform tracks both small-molecule and immunotherapy pipelines in AML.
- Phase I/II trials of thienopyrimidine menin-MLL inhibitors confirmed (DKFZ 2021; UPenn 2022)
- Remarkable clinical efficacy in relapsed/refractory MLL-r and NPM1-mutant AML (MSK 2023)
- Terminal myeloid differentiation observed as primary clinical mechanism of action
- Pinometostat (DOT1L) Phase Ib/II data: modest monotherapy effects, combination rationale supported
- PDX models and primary patient material used for resistance characterization (MSK 2023)
- NPM1 immunopeptidome data signal parallel immunotherapy opportunity (Stanford 2019)
Menin-MLL Inhibitor Pipeline — Key Questions Answered
The menin protein, encoded by the MEN1 tumor suppressor gene, normally functions as a growth suppressor. However, in both NPM1-mutant AML and MLL-rearranged leukemia, menin acts as an obligate oncogenic cofactor. Menin binds directly to MLL1 fusion proteins and to wild-type MLL1 in NPM1-mutant cells, tethering the complex to HOXA cluster and MEIS1 loci to maintain a leukemia-sustaining transcriptional program. Small-molecule disruption of the menin-MLL protein–protein interaction has emerged as a clinically actionable epigenetic strategy.
NPM1 mutation is the most common genetic alteration in acute myeloid leukemia, detected in about 30–35% of adult AML and more than 50% of AML with normal karyotype. MLL/KMT2A rearrangements account for approximately 75% of infant and approximately 10% of adult acute leukemia cases, involving over 80 documented fusion partner genes.
The most clinically advanced class in the retrieved data is the thienopyrimidine series, which has entered Phase I/II clinical trials as single agents that eradicate leukemia in xenograft models of primary leukemic cells belonging to the MLL-rearranged or NPM1-mutant subtypes and are well tolerated with few or no side effects.
Memorial Sloan Kettering Cancer Center (MSK) is by far the dominant assignee, holding a portfolio of at least 9 patent filings across multiple jurisdictions (US, WO, EP, CA, AU) claiming methods of treating NPM1-mutant and MLL-rearranged leukemia using menin-MLL inhibitors and combinations with DOT1L inhibitors. Active and pending filings span 2017–2026, indicating sustained prosecution activity.
Retrieved results identify both genetic and non-genetic resistance mechanisms. Leukemia cells that cannot activate the UTX-dependent transcriptional program (e.g., through UTX loss or mutation) are predicted to be resistant to menin inhibitors. Additionally, KAT6A has been identified as an epigenetic switch regulating non-genetic resistance to menin inhibition, and perturbation of KAT6A was found to reprogram resistant cells to a sensitive state.
Several combination strategies are being actively explored: menin inhibitor combined with DOT1L inhibitor (the most prominently featured combination, with MSK patent claims covering this combination in NPM1-mutant leukemia); menin inhibitor with CDK4/6 inhibitors for resistance rescue via UTX reactivation; menin inhibitor with KAT6A perturbation for acquired resistance; and co-inhibition of HDAC (using chidamide) with menin-MLL interaction showing synergistic killing of MLL-rearranged AML cells.
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References
- High-Affinity Small-Molecule Inhibitors of the Menin-MLL Interaction Closely Mimic a Natural Protein–Protein Interaction — Vanderbilt Specialized Chemistry Center (MLPCN), 2014
- Functional diversity of inhibitors tackling the differentiation blockage of MLL-rearranged leukemia — Bayer AG, 2019
- Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia — Memorial Sloan-Kettering Cancer Center, CA, 2017 [Patent]
- Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia — Memorial Sloan-Kettering Cancer Center, WO, 2017 [Patent]
- Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia — Memorial Sloan-Kettering Cancer Center, EP, 2018 [Patent]
- Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia — Memorial Sloan Kettering Cancer Center, US, 2020 [Patent]
- Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia — Memorial Sloan Kettering Cancer Center, US, 2019 [Patent]
- Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia — Memorial Sloan Kettering Cancer Center, AU, 2024 [Patent]
- Inhibitors of the menin-MLL interaction — Vitae Pharmaceuticals, Inc., EP, 2023 [Patent]
- A Box of Chemistry to Inhibit the MEN1 Tumor Suppressor Gene Promoting Leukemia — University of Freiburg / DKFZ, 2021
- A Molecular Switch between Mammalian MLL Complexes Dictates Response to Menin–MLL Inhibition — The Rockefeller University, 2022
- A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition — Dana-Farber Cancer Institute, 2021
- S125: Non-Genetic Resistance to Menin Inhibition in AML is Reversible by Perturbation of KAT6A — Memorial Sloan Kettering Cancer Center, 2023
- Targeting Menin and CD47 to Address Unmet Needs in Acute Myeloid Leukemia — University of Pennsylvania, 2022
- Current status and future perspectives in targeted therapy of NPM1-mutated AML — University of Perugia, 2022
- MLL-Rearranged Leukemias—An Update on Science and Clinical Approaches — University of Colorado, 2017
- DOT1L Inhibition Sensitizes MLL-Rearranged AML to Chemotherapy — Baylor College of Medicine, 2014
- Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia — Baylor College of Medicine, 2016
- Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia — University of Michigan, 2014
- Small-molecule inhibition of MLL activity by disruption of its interaction with WDR5 — Structural Genomics Consortium, 2012
- Co-inhibition of HDAC and MLL-menin interaction targets MLL-rearranged acute myeloid leukemia cells — Xiamen University, 2019
- MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199 — MD Anderson Cancer Center, 2015
- Acute myeloid leukemia immunopeptidome reveals HLA presentation of mutated nucleophosmin — Stanford University, 2019
- Non-canonical H3K79me2-dependent pathways promote the survival of MLL-rearranged leukemia — University of Chicago, 2021
- ClinicalTrials.gov — Menin Inhibitor Clinical Trial Registry — U.S. National Library of Medicine
- National Institutes of Health — AML Research Resources
- Baylor College of Medicine — Hematology Research
- Structural Genomics Consortium — Open Science Chemical Probes
All data and statistics on this page are sourced from the references above and from PatSnap's proprietary innovation intelligence platform. This report is derived from a limited set of patent and literature records and represents a snapshot of innovation signals within this dataset only — it should not be interpreted as a comprehensive view of the full field, clinical pipeline, or regulatory landscape.
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