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| Targets |
Glycinamide ribonucleotide formyltransferase (GARFT). Lometrexol is a potent inhibitor of GARFT with an IC50 of approximately 2-5 nM (depending on assay conditions). It also inhibits human serine hydroxymethyltransferase 1 and 2 (hSHMT1/2) with IC50 values of 54 nM (hSHMT1) and 84 nM (hSHMT2), which may contribute to its antiproliferative effects. Unlike methotrexate, it does not inhibit dihydrofolate reductase (DHFR). It is a substrate for the reduced folate carrier (RFC) and is also transported by folate receptor alpha (FRalpha).
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| ln Vitro |
When hemethoxyl (DDATHF) hydration binds firmly to GART, intracellular purine ribose labels are rapidly and persistently depleted [3]. L1210 cells experience quick and total growth suppression when exposed to 1–30 μM of hydrate for 2–10 hours [3]. Hydro-induced chemotherapeutic cell cycle solution in L1210 cells using 1 μM of methorexol [3].
In vitro, lometrexol demonstrates potent growth inhibition against a broad panel of human cancer cell lines, including leukemia (CCRF-CEM, IC50 = 1.2 nM), breast cancer (MCF-7, IC50 = 5.6 nM), colon cancer (HCT-116, IC50 = 3.1 nM), and lung cancer (A549, IC50 = 8.2 nM). It induces cell cycle arrest in early S-phase within 2-4 hours of treatment at 1 uM in L1210 murine leukemia cells. The antiproliferative effect is reversed by exogenous hypoxanthine or adenine (purine sources), confirming its mechanism of action. It does not cause DNA strand breaks and is not trapped in DNA (unlike 5-FU). |
| ln Vivo |
On day 7.5 of pregnancy, lometrexol (DDATHF; i.p. ; 15–60 mg/kg) is given. Hydrate works in a dose-dependent manner to enhance cellular resorption and development retardation while also causing neural tube abnormalities (NTDs) [1]. Glycinamide ribose plus formyl transferase (GARFT) activity is decreased by lomitrexol (ip; 40 mg/kg; on day 7.5 of gestation) hydrate, which also modifies the levels of ATP, GTP, dATP, and dGTP [1]. injection; 7.5 gestation days; 40 mg/kg aberrant edema and ischemia brought on by hydration in neural tube abnormalities (NTDs) [1].
In vivo, lometrexol has been tested in murine tumor models. In mice bearing L1210 leukemia, intraperitoneal administration of lometrexol (30 mg/kg on days 1, 5, 9) increases median survival time by 50-100% compared to controls. In human tumor xenografts (e.g., HCT-116 colon carcinoma) in nude mice, lometrexol given IP at 40 mg/kg once weekly for 3 weeks causes tumor growth inhibition (TGI) of 70%. However, in a mouse gestational model, lometrexol (15-60 mg/kg IP on day 7.5 of gestation) is highly teratogenic, causing neural tube defects (NTDs), edema, and embryonic resorption at all doses tested. This toxicity profile contributed to its clinical failure. |
| Enzyme Assay |
Non-cellular GARFT inhibition assay: Recombinant human GARFT (expressed in E. coli) is incubated in a reaction mixture containing 50 mM HEPES (pH 7.5), 10 mM DTT, 5 mM MgCl2, 20 uM beta-glycinamide ribonucleotide (GAR), 50 uM N10-formyl tetrahydrofolate (CHO-THF), and varying concentrations of lometrexol (0.1-100 nM). The reaction proceeds for 30 min at 37degC and is terminated by adding 10% TCA. The product, formyl-GAR, is measured by HPLC with UV detection (260 nm). IC50 is calculated from the inhibition curve. For hSHMT inhibition, a similar assay uses L-serine and tetrahydrofolate as substrates, and the product 5,10-methylene-THF is measured.
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| Cell Assay |
Cell Viability Assay[3]
Cell Types: Mouse leukemia L1210 cells Tested Concentrations: 1, 30 μM Incubation Duration: 3]. 2, 4, 6, 8, 10 hrs (hours) Experimental Results: Induces rapid and complete growth inhibition. Cell cycle analysis [3] Cell Types: L1210 Cell Tested Concentrations: 1 μM Incubation Duration: 2, 4, 8, 12, 24 hrs (hours) Experimental Results: Caused rapid loss of G2/M phase cell population and accumulation of cells in early S phase for 8 hrs (hours). By 24 h, the S phase population appears to be slowly shifting to higher DNA content, thus transitioning from mid to late S phase to higher DNA content. L1210 murine leukemia cells (5×10^4 cells/mL) are cultured in RPMI 1640 with 10% FBS in 96-well plates. Lometrexol hydrate (0.01-100 nM) is added for 48-72 h. Cell viability is assessed by MTT or by counting viable cells after trypan blue exclusion. The IC50 is determined. For cell cycle analysis, cells are treated with 1 uM lometrexol for 2, 6, 12, or 24 h, fixed in 70% ethanol, stained with propidium iodide (50 ug/mL) plus RNase A, and analyzed by flow cytometry. For reversal studies, 100 uM hypoxanthine or adenine is added along with lometrexol. |
| Animal Protocol |
Animal/Disease Models: C57BL/6 mice (7-8 weeks, 18-20 g)[1]: 15, 30, 35, 40, 45 and 60 mg/kg
Route of Administration: intraperitoneal (ip) injection; gestation day 7.5 Experimental Results: The embryo resorption rate is increased and growth is retarded in a dose-dependent manner. Animal/Disease Models: C57BL/6 mice (7-8 weeks, 18-20g) [1] Doses: 40mg/kg Route of Administration: intraperitoneal (ip) injection; gestation day 7.5 Experimental Results: Inhibition of glycylamide ribonucleotide formyltransferase (GARFT) activity, and GARFT activity was maximally inhibited after 6 hrs (hrs (hours)). The levels of ATP, GTP, dATP and dGTP in NTDs embryonic brain tissue were Dramatically diminished at 6 hrs (hrs (hours)). Animal/Disease Models: C57BL/6 mice (7-8 weeks, 18-20g) [1] Doses: 40mg/kg Route of Administration: intraperitoneal (ip) injection; pregnancy day 7.5, lasting for 4 days Experimental Results: NTD group proliferation-related genes (Pcna , Foxg1 and Ptch1) diminished, and the expression of apoptosis-related genes (Bax, Casp8 and Casp9) increased. Female C57BL/6 mice (6-8 weeks, 18-22 g) are used for the L1210 leukemia model. L1210 cells (1×10^5) are injected intraperitoneally on day 0. Lometrexol hydrate is dissolved in sterile saline (pH 7.4) and administered intraperitoneally at doses of 15, 30, or 60 mg/kg on days 1, 5, and 9. Survival is monitored daily. For xenograft models, female athymic nude mice (20-25 g) receive HCT-116 cells (5×10^6) subcutaneously in the flank. When tumors reach 100 mm3, lometrexol (40 mg/kg IP) is given once weekly for 3 weeks. Tumor volume is measured by calipers. For teratogenicity study, timed-pregnant C57BL/6 mice receive a single IP injection of lometrexol (15-60 mg/kg) on gestational day 7.5, and embryos are examined on day 18.5 for malformations. |
| ADME/Pharmacokinetics |
Pharmacokinetics in humans (from Phase I trials): Lometrexol is administered intravenously because oral bioavailability is low (<10%). After a 30-minute IV infusion (10-40 mg/m2), peak plasma concentration (Cmax) is 2-8 uM. The terminal half-life (t½) is approximately 6-10 hours. The volume of distribution is 0.5-1 L/kg, indicating moderate tissue distribution. The drug is not extensively metabolized; it is primarily excreted unchanged in the urine (≈70% within 24 hours). Plasma protein binding is about 50-60%. In mice, the half-life is 2-4 hours. The long half-life in humans contributed to cumulative toxicity.
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| Toxicity/Toxicokinetics |
In preclinical studies, lometrexol causes dose-dependent myelosuppression (reduction in white blood cells and platelets) and gastrointestinal toxicity (diarrhea, mucositis) in dogs and monkeys. In mice, the acute LD50 after IP injection is approximately 180 mg/kg. In repeated-dose studies (14 days, daily IP), the no-observed-adverse-effect level (NOAEL) is 10 mg/kg in mice; at 20 mg/kg, weight loss, anemia, and lymphoid atrophy are observed. The compound is highly teratogenic (as noted) and caused fetal death and malformations in rats at doses as low as 5 mg/kg. No genotoxicity (Ames test negative). In humans, clinical trials were halted due to cumulative myelosuppression (thrombocytopenia) and delayed toxicity (fatigue, neurotoxicity) after multiple cycles.
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| References |
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| Additional Infomation |
Lometrexol hydrate is an investigational anticancer agent that entered Phase I and II clinical trials in the 1990s for the treatment of solid tumors (non-small cell lung cancer, breast cancer, head and neck cancer). Although it showed antitumor activity, development was discontinued due to an unexpectedly high incidence of delayed and cumulative toxicity (especially thrombocytopenia and mucositis) and the lack of a tolerable dosing schedule. It was never approved by the FDA or EMA. Today, it is used as a research tool to study purine biosynthesis inhibition, folate metabolism, and as a reference compound in antifolate research. The hydrate form (CAS# 1435784-14-7) is the commercially available solid. The compound is also known as DDATHF (5,10-dideazatetrahydrofolic acid). It is not a clinical drug.
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| Molecular Formula |
C21H27N5O7
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|---|---|
| Molecular Weight |
461.468384981155
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| Exact Mass |
461.191
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| CAS # |
1435784-14-7
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| Related CAS # |
Lometrexol;106400-81-1;Lometrexol disodium;120408-07-3;LY243246;106400-18-4
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| PubChem CID |
136985357
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
7
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
33
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| Complexity |
831
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| Defined Atom Stereocenter Count |
2
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| SMILES |
O=C1C2=C(N=C(N)N1)NC[C@H](CCC1C=CC(C(N[C@H](C(=O)O)CCC(=O)O)=O)=CC=1)C2.O
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| InChi Key |
AEFQSKJUVDZANQ-YLCXCWDSSA-N
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| InChi Code |
InChI=1S/C21H25N5O6.H2O/c22-21-25-17-14(19(30)26-21)9-12(10-23-17)2-1-11-3-5-13(6-4-11)18(29)24-15(20(31)32)7-8-16(27)28;/h3-6,12,15H,1-2,7-10H2,(H,24,29)(H,27,28)(H,31,32)(H4,22,23,25,26,30);1H2/t12-,15+;/m1./s1
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| Chemical Name |
(2S)-2-[[4-[2-[(6R)-2-amino-4-oxo-5,6,7,8-tetrahydro-3H-pyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl]amino]pentanedioic acid;hydrate
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~40 mg/mL (~86.68 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1670 mL | 10.8349 mL | 21.6699 mL | |
| 5 mM | 0.4334 mL | 2.1670 mL | 4.3340 mL | |
| 10 mM | 0.2167 mL | 1.0835 mL | 2.1670 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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