Dihydrofolate reductase Inhibitors
14 drugsAbout Dihydrofolate reductase
Dihydrofolate reductase (DHFR) is an enzyme crucial for folate metabolism, catalyzing dihydrofolate reduction to tetrahydrofolate, essential for nucleotide and amino acid biosynthesis. By inhibiting DHFR, drugs disrupt DNA and RNA synthesis, hindering cell growth.
Human genetic studies provide strong validation for DHFR as a therapeutic target (max score 0.92), with variants linked to hereditary neoplastic syndrome and inherited cancer-predisposing syndrome. Loss-of-function variants that reduce enzyme activity are associated with increased disease risk, supporting inhibition-based therapies.
DHFR is targeted by 14 FDA-approved small molecule drugs, including METHOTREXATE SODIUM and VYKOURA, primarily for oncology (12 drugs). The first drug was approved in 1953, with the most recent in 2026.
Strategic Insights
ℹ️ How we calculate- phase2 represents biological uncertainty with 48% completion.
Human Genetic Evidence Strong
DHFR has strong genetic support with a maximum score of 0.92 linking it to hereditary neoplastic syndrome.
Strong genetic support increases the probability of clinical success, making DHFR a promising target for further drug development.
Evidence Across Diseases
12 totalGWAS and other genetic studies link DHFR to 12 diseases.
🔗 Colocalization Evidence 20 strong
max H4: 1.00eQTL/pQTL signals for DHFR colocalize with these GWAS traits, providing causal evidence that gene expression changes drive disease risk.
Understanding these scores
Association Score (0-1): Combines all evidence types (genetic, literature, drugs, animal models). Higher = more evidence linking target to disease. This is a ranking heuristic, not a confidence score.
L2G Score: Open Targets uses a machine learning model (Locus-to-Gene) to predict which gene is causal at each GWAS locus. L2G=0.5 means ~50% probability of being the causal gene. Only associations with L2G > 0.05 are included.
Odds Ratio (OR): From gene burden studies (UK Biobank, AstraZeneca PheWAS). Measures how loss-of-function variants affect disease risk. OR<1 = protective (inhibiting target may help), OR>1 = risk (losing function causes disease).
Beta (β): Effect size for continuous traits. β<0 = protective, β>0 = risk.
Clinical Translation (~1.8x): Based on Nelson et al. 2015: drug targets with genetic evidence have ~2x higher success rates in clinical trials. We estimate: Strong support (score ≥0.7) → ~1.8x, Moderate (0.3-0.7) → ~1.3x, Weak → baseline.
Colocalization (H4): Tests whether a GWAS signal and an eQTL/pQTL signal share the same causal variant. H4 is the posterior probability that both traits are associated AND share a causal variant. H4 > 0.8 = strong evidence that gene expression/protein levels drive disease risk. This links genetic variation → gene expression → disease, supporting the target-disease connection.
Top Drugs
Twelve companies have approved drugs targeting DHFR, with Hikma and QILU PHARM HAINAN as top players.
The competitive landscape is moderately fragmented, suggesting relatively low barriers to entry for new DHFR inhibitors.
| Drug | Company | Approved | Indications |
|---|---|---|---|
| JYLAMVO | SHORLA | 2022 | 6 |
| VYKOURA | AVYXA HOLDINGS | 2026 | 5 |
| LEVOLEUCOVORIN CALCIUM | GLAND | 2015 | 4 |
| PEMETREXED | Teva | 2020 | 2 |
| PEMETREXED DISODIUM | ACCORD HLTHCARE | 2022 | 2 |
| XATMEP | AZURITY | 2017 | 2 |
| PEMFEXY | EAGLE PHARMS | 2020 | 2 |
| ALIMTA | Eli Lilly | 2004 | 2 |
| PEMETREXED FOR INJECTION | Dr. Reddy's | - | 2 |
| AXTLE | AVYXA HOLDINGS | 2024 | 2 |
| FOLOTYN | ACROTECH BIOPHARMA | 2009 | 1 |
Drug Modality Landscape
Modalities
Routes of Administration
Dihydrofolate reductase is amenable to small molecule drugs, with oral options available for convenient dosing.
The modality landscape is saturated with small molecules, suggesting an opportunity for novel modalities like PROTACs or biologics.
Clinical Trials 1,807 trials
Completion by Phase
| Phase | Total | Completed | Failed | Active | Completion |
|---|---|---|---|---|---|
| Phase 1 | 469 | 222 | 91 | 156 | 71% |
| Phase 2 | 788 | 300 | 173 | 311 | 63% |
| Phase 3 | 413 | 193 | 49 | 169 | 80% |
| Phase 4 | 137 | 85 | 19 | 31 | 82% |
Top Sponsors
By Modality
Top Conditions
Phase 3 Readout Calendar Pro
8 Phase 3 trials testing approved Dihydrofolate reductase drugs across all sponsors.
Coverage: trials whose intervention is an approved drug targeting Dihydrofolate reductase. Pre-approval candidates with development codes (e.g. AZD0901, MK-7240) are not yet linked. Anchored on CT.gov primary completion date.
Drug Approval Timeline (1959 - 2026)
DHFR has a long approval history spanning 74 years, from 1953 to 2026.
The continued approval of DHFR inhibitors suggests sustained interest, but also potential market saturation requiring differentiated products.
Pro Intelligence Preview
Deep insights for drug target analysis
Competitive Landscape
- • 12 companies competing
- • Market share by company
Full Drug Portfolio
- • All 14 approved drugs
- • Approval dates & indications
Genetic Validation
- • Full genetic evidence table
- • Effect sizes & directions
Approval Timeline
- • Full 14-drug timeline
- • First-of-modality markers
Clinical Trials Analysis
- • Competition: High (15 sponsors)
- • Success rates by condition
Full summary • All drugs • Genetic evidence • Trials • Timeline
How We Calculate These Metrics
Target Attractiveness Score
A 0-100 score based on trial activity, sponsor diversity, and completion rates. Calculated from 1145 clinical trials targeting Dihydrofolate reductase.
Completion rate: Percentage of trials that reached their planned endpoint. Trials terminated early, withdrawn, or suspended are not counted—these often indicate safety issues, lack of efficacy, or strategic pivots.
- Highly Attractive (80+): High trial activity, many sponsors, strong completion rates
- Attractive (60-79): Good trial activity and validation
- Moderate (40-59): Moderate interest from sponsors
- Low (under 40): Limited trial activity or validation concerns
Strategic Insights
Auto-generated insights based on trial analytics including competition intensity, white space opportunities, modality shifts, and failure patterns. We analyze trial sponsors, phases, indications, and outcomes.
Risk Signals
- High Competition: Many sponsors competing for this target (may reduce market opportunity)
- High Failure Risk: Low trial completion rates suggest development challenges
- Low Validation: Limited trial activity or poor outcomes indicate uncertain viability
- White Space Available: Underexplored indications present opportunities