DHFR dihydrofolate reductase
ENSG00000228716 · protein coding · Open Targets profile
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. {ECO:0000269|PubMed:12096917, ECO:0000269|PubMed:15039552, ECO:0000269|PubMed:17569517, ECO:0000269|PubMed:19196009, ECO:0000269|PubMed:19478082, ECO:0000269|PubMed:21876184, ECO:0000269|PubMed:21876188, ECO:0000269|PubMed:22235121, ECO:0000269|PubMed:9719595}.
Each band is a group of drugs. It runs from the kind of drug on the left to the furthest stage that drug has reached in any disease on the right. Thicker bands mean more drugs.
Approved bands are highlighted. Withdrawn means the drug was pulled from the market or from development. A combined phase counts as the later one (Phase 1/2 is shown as Phase 2). Hover a band for the drug names. Source: Open Targets Platform, fetched live.
Each row is a cancer, strongest overall evidence first. The two dots show how strong the inherited (germline) and tumour-mutation (somatic) evidence is; the line between them is the gap.
Scores run from 0 (no evidence) to 1 (strongest). A missing dot at 0 means Open Targets holds no evidence of that kind. Source: Open Targets Platform, fetched live.
Tractability
- Small molecule
- Approved Drug, Structure with Ligand, High-Quality Ligand, High-Quality Pocket, Druggable Family
- PROTAC
- Database Ubiquitination, Half-life Data, Small Molecule Binder
gnomAD loss of function constraint: o/e 0.44290000200271606 (upper bound 0.7330999970436096). Low values mean loss of function is poorly tolerated, a safety flag for inhibition.
Who runs trials of these drugs
Principal investigators and study chairs on 400 registry trials, updated in the last three years, of the most advanced drugs against DHFR (methotrexate, pemetrexed, pemetrexed tromethamine, pralatrexate, piritrexim), ranked by Phase 2+ trials. Live from ClinicalTrials.gov.
- Elias JabbourM.D. Anderson Cancer Center · 4 of 4 trials Phase 2+Ph2NCT03263572 · Blinatumomab, Methotrexate, Cytarabine, and Ponatinib in Treating Patients With Philadelphia Chromosome-Positive, or BCR-ABL Positive, or Relapsed/Refractory, Acute Lymphoblastic Leukemiabrief
- Amar GajjarSt. Jude Children's Research Hospital · 2 of 2 trials Phase 2+
- Anjali S AdvaniSWOG Network Cancer Center · 2 of 2 trials Phase 2+
- Bristol-Myers SquibbBristol-Myers Squibb · 2 of 2 trials Phase 2+
- Farhad Ravandi-KashaniSWOG Cancer Research Network · 2 of 2 trials Phase 2+
- Ibrahim AldossCity of Hope Medical Center · 2 of 2 trials Phase 2+
- li ZhangSun Yat-Sen University Cancer Center · 2 of 2 trials Phase 2+
- Linda MartinUniversity of Virginia · 2 of 2 trials Phase 2+
- Luhua (Michael) WangM.D. Anderson Cancer Center · 2 of 2 trials Phase 2+
- Marie BleakleyFred Hutch/University of Washington Cancer Consortium · 2 of 2 trials Phase 2+
- Seth E. KarolSt. Jude Children's Research Hospital · 2 of 2 trials Phase 2+
- Zhenyu PanJinshan Hospital Fudan University · 2 of 2 trials Phase 2+
- Anne S TsaoSWOG Cancer Research Network · 1 of 2 trials Phase 2+
- Rahul LakhotiaNational Cancer Institute (NCI) · 1 of 2 trials Phase 2+
- Tong ChenHuashan Hospital · 1 of 2 trials Phase 2+
Registry trials of methotrexate, pemetrexed, pemetrexed tromethamine, pralatrexate, piritrexim updated in the last three years, counted by the country group of their listed sites. A trial with sites in several groups counts in each; 223 of 381 have all sites in one country.
Site counts are not patients per country, and trials registered only outside ClinicalTrials.gov are not covered. Where sites are is a fact about the record, not a judgement of its quality. Europe is the EU and EEA, the UK and Switzerland. 19 trials list no sites and are left out. Source: ClinicalTrials.gov, fetched live.
514 trials of drugs against DHFR were stopped early; 10 of the 200 most recent give no reason
Terminated, withdrawn and suspended interventional trials of methotrexate, pemetrexed, pemetrexed tromethamine, pralatrexate, piritrexim, newest update first, live from ClinicalTrials.gov. Each reason is quoted exactly as the registry gives it; we do not sort reasons into safety, efficacy or business. Dates are the last registry update. Showing the 25 most recent of 514.
- suspended · 2026-11-10 · National Cancer Institute (NCI) · pemetrexed“Placed on voluntary hold to new recruitment pending modification to combination monoclonal antibody treatment.”
- terminated · 2026-10-30 · Tufts Medical Center · pemetrexed“Futility”
- suspended · 2026-10-27 · National Cancer Institute (NCI) · Methotrexate“Other - Extend the observation period for current patients”
- terminated · 2026-10-19 · Boston Children's Hospital · Methotrexate“Funding terminated”
- terminated · 2026-10-08 · Jin Hyoung Kang · Pemetrexed“Slow accrual; enrollment was closed after 14 of 28 planned participants.”
- terminated · 2026-09-29 · Sanofi · Pemetrexed“Early discontinuation based on strategic sponsor decision not driven by any safety concerns”
- withdrawn · 2026-09-24 · Case Comprehensive Cancer Center · matched by the registry's drug synonyms“PI left institution”
- terminated · 2026-09-23 · Hackensack Meridian Health · Pemetrexed“Slow Accrual”
- terminated · 2026-09-18 · Pusan National University Yangsan Hospital · matched by the registry's drug synonyms“Poor accrual due to increased use of alternative neoadjuvant treatment options.”
- terminated · 2026-09-16 · Jennifer Amengual · Pralatrexate“Lack of funding and recruitment complications caused by COVID-19”
- terminated · 2026-09-11 · Merck Sharp & Dohme LLC · Pemetrexed“MK-7684A-007 was terminated early due to futility. A non-submission CSR, not intended to support any registration, was issued; therefore, an abbreviated CSR was generated.”
- terminated · 2026-09-08 · ETOP IBCSG Partners Foundation · matched by the registry's drug synonyms“Completion of recruitment was not feasible as accrual was slower than anticipated. Even if a benefit for denosumab could be shown, these results would be of very limited clinical impact by the time they would be available”
- terminated · 2026-09-03 · GlaxoSmithKline · Pemetrexed+ (carboplatin or cisplatin)“Operational challenges”
- terminated · 2026-08-14 · Astellas Pharma Global Development, Inc. · Pemetrexed“Lack of clinical benefit”
- terminated · 2026-07-30 · M.D. Anderson Cancer Center · Methotrexate“the study was closed early due to competing trials”
- terminated · 2026-07-22 · University of Utah · Pemetrexed“Closed due to slow accrual”
- terminated · 2026-07-20 · National Institute of Allergy and Infectious Diseases (NIAID) · matched by the registry's drug synonyms“The study is being closed early due to insufficient participant enrollment across study sites.”
- terminated · 2026-07-13 · NRG Oncology · Pemetrexed, Pemetrexed Disodium“Permanent Administrative Closure”
- withdrawn · 2026-06-22 · ImmunityBio, Inc. · Nab-paclitaxel (squamous) OR Pemetrexed (nonsquamous), Pemetrexed (nonsquamous)“Sponsor decision”
- terminated · 2026-06-17 · Weill Medical College of Cornell University · Methotrexate“The study was terminated due to slow accrual.”
- terminated · 2026-06-17 · Novartis Pharmaceuticals · pemetrexed“Results of primary analysis showed addition of canakinumab to combination treatment did not improve tumor response or overall survival; the decision to stop the trial was not due to safety concerns”
- terminated · 2026-06-10 · National Institute of Allergy and Infectious Diseases (NIAID) · matched by the registry's drug synonyms“The study was closed due to continued enrollment hurdles.”
- terminated · 2026-05-26 · ImmunityBio, Inc. · Cisplatin/Carboplatin + Pemetrexed + Pembrolizumab + NAI, Cisplatin/Carboplatin + Pemetrexed + Atezolizumab + NAI, Drug: Cisplatin/Carboplatin and Pemetrexed plus Pembrolizumab, Cisplatin/Carboplatin and Pemetrexed plus Atezolizumab“There are no longer active subjects on QUILT-2.023. Data will be entered into clinicaltrials.gov within 1 year of the primary completion date.”
- terminated · 2026-05-22 · Pfizer · pemetrexed“The trial was terminated for strategic business reasons; the decision was not based on any safety and/or efficacy concerns.”
- terminated · 2026-05-15 · Iovance Biotherapeutics, Inc. · Pemetrexed“After reviewing the available safety and efficacy data to date, Iovance concluded that the study reached the required number of events for evaluation of study endpoints.”
Paediatric incentives and obligations for DHFR's drugs
For methotrexate, pemetrexed, pemetrexed tromethamine, pralatrexate, piritrexim: what EMA and FDA publish about paediatric plans, orphan status and pediatric approvals, and how many registered studies take children. Each line is a yes, no or not published fact from the record linked under it; none of it is a forecast.
- FDA pediatric target list: no · DHFR is not on the listRule: Target is on FDA's Pediatric Molecular Target List (relevant targets). Source: FDA Pediatric Molecular Target List (Listed as February 2026 on the FDA Pediatric Oncology page; the file served is 9.7.22_the_relevant_molecular_target_list.xlsx, whose Summary of Changes sheet is headed 'SEPTEMBER 2022 UPDATE' (footnote date 2022-09-01)), 2026-11-11
- EU paediatric investigation plan: yes · EMEA-000619-PIP02-10 (pralatrexate, Treatment of Hodgkin lymphoma;Treatment of lymphoblastic non-Hodgkin lymphoma;Treatment of mature B-cell non-Hodgkin lymphoma;Treatment of peripheral T-cell lymphoma (nodal, other extranodal and leukaemic/disseminated)): P: decision agreeing on a investigation plan, with or without partial waiver(s) and or deferral(s), 2 Dec 2010Rule: An EMA PIP decision (agreement, modification or waiver) lists the drug as its active substance, exact name. Source: EMA EMEA-000619-PIP02-10, 2026-11-11
- EU orphan designation: yes · EU/3/25/3135 positive 22 Aug 2025: Treatment of primary large B-cell lymphoma of immune-privileged sites; EU/3/25/3089 positive 18 Jul 2025: Treatment of non-syndromic inherited retinal dystrophies of the rod-dominant phenotype; EU/3/20/2276 positive 4 Jun 2020: Treatment of retinal detachment; EU/3/16/1723 positive 29 Aug 2016: Treatment of alkaptonuria; +5 moreRule: An EU orphan designation lists the drug as its active substance (exact name) or belongs to a medicine that does; withdrawn and expired designations are listed with their status. Source: EMA data download (dated snapshot), 2026-11-11
- Authorised in the EU: yes · Pemetrexed medac: withdrawn since 26 Nov 2015; Nordimet: authorised since 18 Aug 2016; Pemetrexed Baxter: withdrawn since 9 Dec 2022; Jylamvo: authorised since 29 Mar 2017; +12 moreRule: An EMA medicine record lists the drug as its active substance or INN, exact name; national-only authorisations are not in this file. Source: EMA data download (dated snapshot), 2026-11-11
- FDA orphan designation: not published · FDA's orphan designation database turns away automated requests, so this app does not read it; search it by hand at the linkRule: Would be: an FDA orphan designation names the drug. Source: FDA orphan designations search
- FDA pediatric oncology approval: yes · Methotrexate, 7 Dec 1953: Treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy regimen; Methotrexate, 7 Dec 1953: Prophylaxis and treatment of meningeal leukemia in adult and pediatric patients; Methotrexate, 7 Dec 1953: Treatment of adults and pediatric patients with Non-Hodgkin lymphoma; +1 moreRule: FDA's Pediatric Oncology Drug Approvals table names the drug. Source: FDA Pediatric Oncology Drug Approvals (content current as of 2026-03-03), 2026-11-11
- Registered studies open to children: yes · 744 interventional studies of methotrexate, pemetrexed, pemetrexed tromethamine, pralatrexate, piritrexim include patients under 18; 136 are recruiting, not yet recruiting or activeRule: The registry's age group includes Child (birth to 17 years), which also counts studies that set no minimum age. Source: ClinicalTrials.gov search, 2026-11-11
Rare pediatric disease voucher. FDA, content current as of 29 Apr 2026: “As of February 3, 2026, enactment of the Consolidated Appropriations Act, 2026, the rare pediatric disease PRV program will sunset after September 30, 2029. FDA may not award any PRVs under this program after September 30, 2029.” Voucher sale prices are not shown here; they appear only as company-reported news. FDA: Rare Pediatric Disease Designation and Priority Review Voucher Programs
All 8 drugs and clinical candidates as a table
Each drug, stage and indication links to its Open Targets record, where the trials and approvals behind it are listed. Salt forms (for example a mesylate) are listed as Open Targets records them, as separate entries.