Protein / target
Dihydrofolate reductase
Protein at a glance
Biological role
MRNA regulatory element binding translation repressor activity
Primary system
Nervous system
Strongest disease association
Inherited cancer-predisposing syndrome
Therapeutic maturity
Clinically validated target
Druggability
Small molecule
Clinical development
8 approved · 1 in clinical development
Derived from structured UniProt, Open Targets and literature data on this page.
Protein profile
Canonical identity and biological annotation from UniProt.
Function
Catalyzes the reduction of 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate in a NADPH-dependent manner (PubMed:12096917, PubMed:15039552, PubMed:17569517, PubMed:19196009, PubMed:19478082, PubMed:21876184, PubMed:9719595). Key enzyme in folate metabolism. Contributes to the nuclear and mitochondrial de novo thymidylate biosynthesis pathway (PubMed:21876188, PubMed:22235121). Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFR2
Subcellular location
Domains and Gene Ontology detail (24)Hide
Domains & features
Gene Ontology
- Ccytosol
- Cmitochondrion
- Cnucleus
- Creplication fork
- Fdihydrofolate reductase activity
- Ffolic acid binding
- FmRNA binding
- FmRNA regulatory element binding translation repressor activity
- FNADP binding
- FNADPH binding
- Fsequence-specific mRNA binding
- P'de novo' pyrimidine nucleobase biosynthetic process
Biological roles
What this protein does, drawn together from its UniProt function, Gene Ontology terms and Reactome pathways.
View supporting evidenceHide supporting evidence
Metabolic enzyme activity
- ·dihydrofolate metabolic process
- ·folic acid metabolic process
- ·one-carbon metabolic process
- ·tetrahydrofolate metabolic process
Transcriptional regulation
- ·G1/S-Specific Transcription
View underlying pathways (3)Hide underlying pathways
Concepts derived from UniProt GO Reactome — each badge above shows which sources supported that role.
Interaction neighbourhood
Proteins with the strongest functional or physical association. Node size and line weight reflect STRING confidence; hover or select a partner to inspect one association.
Functional and physical associations from STRING v12.0. Only associations with this protein are drawn — partner-to-partner links are not part of this evidence.
Drugs targeting this protein
Whether each drug engages this protein directly or through a complex, and how many other targets are recorded for it. Direct binders with few recorded targets are listed first.
Dihydrofolate reductase inhibitor
Appears in clinical studies involving malignant pleural mesothelioma, mesothelioma, non-small cell lung carcinoma, neoplasm
Dihydrofolate reductase inhibitor
Appears in clinical studies involving breast cancer, leptomeningeal metastasis, non-Hodgkin lymphoma, rheumatoid arthritis
ChEMBL mechanism, action type and target identity. Open Targets clinical status and indications.
Translational evidence
Why this target matters therapeutically — disease associations, drugs in development, tractability and safety, from Open Targets.
Strongest genetic associations
Human genetic evidence — the most direct causal link between this target and a disease.
Highest-confidence therapeutic associations
Diseases where a drug acting on this target has already reached clinical development.
Highest overall evidence
Remaining associations by Open Targets' aggregated evidence score.
Show all associationsHide all associations
Open Targets ranks 647 associations for this target and we store the top 10 by aggregated score. The long tail is largely literature co-mention and RNA-expression evidence, not evidence that this target drives those diseases.
Known drugs · 9 total
mesothelioma · non-small cell lung carcinoma
lung cancer · fungal infectious disease · breast cancer
breast cancer · leptomeningeal metastasis · non-Hodgkin lymphoma
lung large cell carcinoma
T-cell non-Hodgkin lymphoma · peripheral T-cell lymphoma, not otherwise specified · mature T-cell and NK-cell non-Hodgkin lymphoma
malignant pleural mesothelioma · mesothelioma · non-small cell lung carcinoma
lung large cell carcinoma · adenocarcinoma · mesothelioma
non-small cell lung carcinoma · non-small cell lung carcinoma · malignant pleural mesothelioma
urinary bladder carcinoma · urothelial carcinoma
Tractability
Safety liabilities
Clinical trials
Trials of drugs that target this protein — reached indirectly through those drugs, so a trial listed here studies the drug, not the protein.
Show remaining trials (24)Hide
ClinicalTrials.gov via the drug-target graph.
Forefront confidence
Our own weighting of the evidence behind each disease association. Human genetics and clinical evidence count for most; literature co-mention counts for little, because two entities sharing an abstract is not evidence that one drives the other.
This ranking differs from Open Targets' own: re-weighting moves genetically-evidenced diseases above more heavily co-mentioned ones. The evidence agreement range shows how closely the independent evidence families agree — it is not a statistical confidence interval, and nothing here is fitted to outcome data. Derived from Open Targets evidence types under Forefront weighting; the underlying per-type scores are shown above so the calculation can be checked.
What's happening now
Recent activity around this target, drawn from one canonical event stream. Every item is reached through 2 drugs that target this protein, so each event is news about that drug rather than about the protein directly.
- Withdrawn from market
Market withdrawal: Pemetrexed Sandoz (EMA)
- New publicationPhase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor‒Resistant, <i>EGFR</i>-Mutant, Metastatic Nonsquamous Non-Small Cell Lung Cancer.
- Withdrawn from market
Market withdrawal: Ciambra (EMA)
- Safety communication
Drug Safety Update: Methotrexate: advise patients to take precautions in the sun to avoid photosensitivity reactions
- New publicationPembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study.
- New publicationAtezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial.
- New publicationTargeting immunometabolism as an anti-inflammatory strategy.
- New publicationEfficacy and safety of adalimumab every other week versus methotrexate once weekly in children and adolescents with severe chronic plaque psoriasis: a randomised, double-blind, phase 3 trial.
- New publicationAdalimumab plus Methotrexate for Uveitis in Juvenile Idiopathic Arthritis.
- Regulatory approval
Approval: Jylamvo (EMA)
- New publicationOsimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer.
- Regulatory approval
Approval: Nordimet (EMA)
Objective event titles are shown unmodified; the event kind and significance line are derived from structured fields. Forefront AttentionEvent stream aggregating Europe PMC Regulatory filings ClinicalTrials.gov.