Alzheimer's Disease Histone Methylation and Epigenetic Writer Companies

Overview

Overview

This category page consolidates biotechnology and pharmaceutical companies developing histone methyltransferase (HMT) modulators, histone demethylase (HDM/LSD) inhibitors, and broader epigenetic writer/eraser mechanisms for Alzheimer's disease. These approaches target the "writers" (enzymes that add methyl marks) and "erasers" (enzymes that remove methyl marks) of epigenetic regulation — a key driver of gene expression dysregulation in neurodegeneration.

This page is distinct from (but related to) the [Alzheimer's Disease HDAC and Epigenetic Inhibitor Companies](/companies/ad-hdac-epigenetic-inhibitor-companies) page, which covers HDAC inhibitors (deacetylase inhibitors), BET bromodomain inhibitors, and reader domain inhibitors. While HDACs remove acetyl marks, HMTs and HDMs regulate methylation marks — a complementary epigenetic mechanism.

Key Therapeutic Approaches

| Approach | Description | Companies |
|----------|-------------|-----------|
| EZH2 Inhibitors | H3K27me3 writers (PRC2 complex) | Epizyme, Constellation/Ultragenyx |
| DOT1L Inhibitors | H3K79me2 writers | Imago Biosciences, Constellation |
| KDM1A/LSD1 Inhibitors | H3K4/K9 demethylases | Oryzon Genomics, GSK |
| PRMT5 Inhibitors | Type II arginine methyltransferases | Accent Therapeutics, GSK |
| JMJD3/KDM6B Inhibitors | H3K27me3 demethylases | Roche, BMS |

EZH2 and H3K27 Methylation Inhibitors

Epizyme Inc.

• Focus: EZH2 inhibitor development for oncology and CNS applications
• Lead Candidate: Tazemetostat (Tazverik/Ezorkspace)
• Mechanism: EZH2 is the catalytic subunit of PRC2 that tri-methylates H3K27 (H3K27me3). In AD, aberrant H3K27me3 accumulation represses synaptic plasticity genes. EZH2 inhibition restores expression of memory-related genes.
• Indication: Alzheimer's disease (exploratory), oncology
• Stage: Approved for epithelioid sarcoma and follicular lymphoma; AD preclinical
• Notes: Originally oncology-focused but exploring neurodegenerative applications. Partnered with Roche on combination approaches.

Constellation Pharmaceuticals (Ultragenyx)

• Focus: EZH2 and DOT1L dual inhibitors
• Lead Candidates: CPI-0209 (EZH2 inhibitor), CPI-1809 (dual EZH2/DOT1L)
• Mechanism: Combined EZH2 (H3K27) and DOT1L (H3K79) inhibition for enhanced epigenetic modulation
• Indication: Alzheimer's disease, oncology
• Stage: Preclinical
• Notes: Constellation was acquired by Ultragenyx in 2023. Pipeline includes CNS applications for epigenetic modulators.

C4 Therapeutics

• Focus: Molecular glue degraders targeting epigenetic writers
• Lead Candidate: CFT-8634 (RET degrader) — not directly EZH2 but related platform
• Mechanism: Using Molecular glue technology to degrade EZH2 and other epigenetic targets
• Indication: Alzheimer's disease (exploratory), oncology
• Stage: Discovery
• Notes: DegrambulX platform targets epigenetic writers for degradation rather than inhibition

DOT1L and H3K79 Methylation Inhibitors

Imago Biosciences

• Focus: DOT1L inhibitor development
• Lead Candidate: IMG-7289 (BME-109)
• Mechanism: DOT1L methylates H3K79 (H3K79me2), which is involved in transcription elongation and DNA damage response. In AD, DOT1L activity is dysregulated, affecting neuronal survival pathways.
• Indication: Alzheimer's disease, myelofibrosis
• Stage: Preclinical (CNS), Phase 1/2 (oncology)
• Notes: Acquired by Merck (MSD) in 2022 for $1.35B. Exploring CNS applications for DOT1L inhibition.

LSD1/KDM1A and Histone Demethylase Inhibitors

Oryzon Genomics SA

• Focus: LSD1/KDM1A and MAO-B dual inhibitors
• Lead Candidate: Iadademstat (ORY-2001)
• Mechanism: LSD1 (KDM1A) demethylates H3K4me1/2 and H3K9me1/2 — key marks for gene activation and repression. In AD, LSD1 overactivity contributes to synaptic gene silencing. Dual LSD1/MAO-B inhibition provides neuroprotection.
• Indication: Alzheimer's disease, Parkinson's disease
• Stage: Phase 2 (LIGHT trial for AD)
• Notes: Spanish biotech (Madrid) with proprietary epigenetics platform. ORY-2001 has shown cognitive improvement in AD models.

GSK (GlaxoSmithKline)

• Focus: LSD1/KDM1A inhibitor development
• Lead Candidates: GSK2879552, GSK-LSD1
• Mechanism: Selective LSD1 inhibition for epigenetic correction in neurodegenerative disease
• Indication: Alzheimer's disease, oncology
• Stage: Preclinical/Phase 1
• Notes: Multiple LSD1 programs in development. Partnered with various academic groups for CNS applications.

Cytozin Inc.

• Focus: KDM1A/LSD1 inhibitors for neuroinflammation
• Lead Program: CYT-387 (novel LSD1 modulator)
• Mechanism: Modulate inflammatory gene expression through LSD1 inhibition
• Indication: Alzheimer's disease
• Stage: Discovery
• Notes: Emerging biotech focused on epigenetic immunomodulation

PRMT5 and Arginine Methylation Inhibitors

Accent Therapeutics

• Focus: PRMT5 and type I/II arginine methyltransferase inhibitors
• Lead Candidate: ATX-002 (PRMT5 inhibitor)
• Mechanism: PRMT5 mediates symmetric dimethylation of arginine (H3R2me2s, H4R3me2s), critical for splicing and transcription. PRMT5 is elevated in AD brains and contributes to tau pathology.
• Indication: Alzheimer's disease, oncology
• Stage: Discovery/Preclinical
• Notes: Founded by scientists from MIT and Dana-Farber. Raised $40M Series B in 2021.

GSK (GlaxoSmithKline)

• Focus: PRMT5 inhibitor programs
• Lead Candidate: GSK-3206308 (PF-06839234)
• Mechanism: PRMT5 inhibition for modulating splicing and transcription dysregulation in AD
• Indication: Alzheimer's disease, oncology
• Stage: Discovery/Preclinical
• Notes: Multiple PRMT5 programs across therapeutic areas

JMJD3/KDM6B and H3K27 Demethylase Inhibitors

Roche

• Focus: JMJD3/KDM6B inhibitor development
• Mechanism: JMJD3 (KDM6B) demethylates H3K27me3 to activate gene expression. While demethylases are typically activating, JMJD3 overactivity in AD can paradoxically repress neuroprotective genes.
• Indication: Alzheimer's disease
• Stage: Discovery
• Notes: Academic partnerships for KDM6B targeting in neurodegeneration

BMS (Bristol Myers Squibb)

• Focus: KDM6B/JMJD3 inhibitor programs
• Mechanism: Modulate H3K27me3 dynamics to restore synaptic gene expression
• Indication: Alzheimer's disease
• Stage: Discovery
• Notes: Part of broader epigenetic drug discovery efforts

Pipeline Overview

| Company | Drug/Program | Mechanism | Phase | Indication |
|---------|--------------|-----------|-------|-------------|
| Epizyme | Tazemetostat | EZH2 (H3K27me3) | Approved (oncology)/Preclinical (AD) | AD |
| Constellation/Ultragenyx | CPI-0209 | EZH2 | Preclinical | AD |
| Imago (Merck) | IMG-7289 | DOT1L (H3K79me2) | Phase 1/2 | AD/oncology |
| Oryzon Genomics | Iadademstat (ORY-2001) | LSD1/KDM1A + MAO-B | Phase 2 | AD |
| GSK | GSK2879552 | LSD1/KDM1A | Preclinical/Phase 1 | AD |
| Accent Therapeutics | ATX-002 | PRMT5 | Discovery | AD |
| GSK | GSK-3206308 | PRMT5 | Discovery | AD |
| Roche | JMJD3 program | KDM6B | Discovery | AD |
| BMS | KDM6B program | KDM6B | Discovery | AD |

Mechanism of Action

Epigenetic Writers and Erasers in Alzheimer's Disease

Histone Methylation Overview:

| Mark | Function | Writer (HMT) | Eraser (HDM) | Role in AD |
|------|----------|--------------|--------------|------------|
| H3K4me3 | Gene activation | MLL3/4, SETD1A/B | KDM5A/B | Reduced at synaptic genes in AD |
| H3K9me3 | Gene repression | SUV39H1, G9a | JmjC family (KDM4) | Increased at neuroprotective genes |
| H3K27me3 | Gene repression | EZH2 | JMJD3/KDM6B | Abnormal accumulation in AD |
| H3K79me2 | Transcription elongation | DOT1L | Unknown | Dysregulated in AD |
| H3R2me2 | Splicing regulation | PRMT5 | Unknown | Promotes tau pathology |

EZH2 Inhibition in AD

EZH2 is the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), which tri-methylates H3K27. In AD:

• H3K27me3 accumulation represses synaptic plasticity genes (BDNF, Arc, c-Fos)
• EZH2 inhibitors restore expression of memory-related genes
• Benefits: Improved synaptic plasticity, cognitive function in preclinical models
• Challenge: EZH2 has both protective and pathogenic roles — timing matters

DOT1L Inhibition in AD

DOT1L methylates H3K79, regulating transcription elongation and DNA damage response:

• H3K79me2 dysregulation affects neuronal survival pathways
• DOT1L inhibitors may restore proper transcription programs
• Clinical potential: Early-stage, primarily oncology-focused

LSD1/KDM1A Inhibition in AD

LSD1 (also known as KDM1A) is a flavin-dependent histone demethylase:

• Targets: H3K4me2 (activation mark), H3K9me2 (repression mark)
• In AD: LSD1 overactivity silences synaptic and mitochondrial genes
• Benefits: Restores synaptic gene expression, reduces neuroinflammation
• Dual-action: Some LSD1 inhibitors also inhibit MAO-B for additional neuroprotection

PRMT5 Inhibition in AD

PRMT5 is a type II arginine methyltransferase:

• Symmetric dimethylation of arginine residues on histones
• In AD: PRMT5 elevation contributes to tau pathology and splicing defects
• Benefits: May reduce tau phosphorylation and improve RNA splicing
• Challenge: PRMT5 has essential functions — therapeutic window needed

KDM6B/JMJD3 Inhibition in AD

JMJD3 (KDM6B) demethylates H3K27me3:

• Normally: Activates developmental genes by removing repressive marks
• In AD: Paradoxical overactivity can dysregulate gene programs
• Modulation: Rather than full inhibition, precise modulation needed

Cross-Links

• [Alzheimer's Disease HDAC and Epigenetic Inhibitor Companies](/companies/ad-hdac-epigenetic-inhibitor-companies)
• [Alzheimer's Disease Epigenetic and Metabolic Therapy Companies](/companies/ad-epigenetic-metabolic-therapy-companies)
• [Epigenetics in AD](/mechanisms/epigenetics-ad)
• [Tau Pathology and Therapeutics](/mechanisms/tau-pathology-therapeutics)
• [Synaptic Plasticity Mechanisms](/mechanisms/synaptic-plasticity)
• [Neuroinflammation Pathway](/mechanisms/neuroinflammation-pathway)

References