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.
Dihydrofolate reductase 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 Dihydrofolate reductase 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 |
|---|---|---|---|
| METHOTREXATE SODIUM PRESERVATIVE FREE | Hikma | 1959 | 6 |
| TREXALL | Teva | 2001 | 6 |
| LEVOLEUCOVORIN CALCIUM | INGENUS PHARMS LLC | 2015 | 4 |
| PEMETREXED DISODIUM | Apotex | 2022 | 2 |
| PEMFEXY | EAGLE PHARMS | 2020 | 2 |
| AXTLE | AVYXA HOLDINGS | 2024 | 2 |
| PEMETREXED | SHILPA | 2020 | 2 |
| ALIMTA | Eli Lilly | 2004 | 2 |
| XATMEP | AZURITY | 2017 | 2 |
| FOLOTYN | ACROTECH BIOPHARMA | 2009 | 1 |
| PEMETREXED FOR INJECTION | Dr. Reddy's | - | - |
Dihydrofolate reductase 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.
Dihydrofolate reductase Clinical Trials 1,825 trials
Phase 1-4 trials started in 2008 or later that test an FDA-approved drug acting on Dihydrofolate reductase. Source: ClinicalTrials.gov. How we count
Completion by Phase
| Phase | Total | Completed | Stopped | Active | Completion |
|---|---|---|---|---|---|
| Phase 1 | 466 | 204 | 99 | 162 | 67% |
| Phase 2 | 813 | 306 | 180 | 324 | 63% |
| Phase 3 | 418 | 201 | 51 | 166 | 80% |
| Phase 4 | 128 | 77 | 19 | 31 | 80% |
Top Sponsors
By Modality
Top Conditions
Top Drugs
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.
Dihydrofolate reductase 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
- • 13 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
- • Sponsors: 632 (226 companies)
- • Completion rates by condition
Full summary • All drugs • Genetic evidence • Trials • Timeline
How We Count Trials
- Trials: phase 1-4 interventional trials on ClinicalTrials.gov that started in 2008 or later and test an FDA-approved drug acting on Dihydrofolate reductase. A trial counts if an approved drug acting on Dihydrofolate reductase is in any arm, including as a comparator, and a trial that tests two such drugs counts once. Trials that test only unapproved drugs are not counted. A trial listed as phase 1/2 counts as phase 1, and phase 2/3 as phase 2.
- Active: recruiting, not yet recruiting, enrolling by invitation, or active and no longer recruiting.
- Completion rate: of the trials that have ended, the share marked Completed rather than Terminated or Withdrawn. Completed means the trial ended as planned; it does not mean the drug worked. Suspended trials are not counted as ended.
- Stopped: terminated or withdrawn. Trials stop for many reasons, including slow enrolment and business decisions, not only safety or efficacy.
- Sponsors: the lead sponsor of each trial. Companies are the sponsors ClinicalTrials.gov classes as industry; the rest are universities, hospitals, cooperative groups, government bodies and individuals.