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| Targets |
Lometrexol targets glycinamide ribonucleotide formyltransferase (GARFT), a key enzyme in the de novo purine biosynthesis pathway. It also inhibits human Serine hydroxymethyltransferase1/2 (hSHMT1/2). By inhibiting GARFT, it blocks the synthesis of purine nucleotides, leading to inhibition of DNA and RNA synthesis, and ultimately cell death.
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| ln Vitro |
Purine ribonucleotides inside cells are rapidly and persistently depleted when lometrexol (DDATHF) binds firmly to GART [3]. L1210 cells experience quick and total growth suppression when exposed to 1–30 μM of methorexol for 2–10 hours [3]. Mouse leukaemia L1210 cells undergo cell cycle arrest when exposed to 1 μM of lometrexol for 2 to 24 hours [3].
In vitro, Lometrexol is a potent inhibitor of GARFT and hSHMT1/2. It shows cytotoxicity against CCRF-CEM cells with an IC50 of 0.07 μM in the absence of hypoxanthine and presence of thymidine. It inhibits de novo purine synthesis, leading to cell cycle arrest and apoptosis. Its anticancer activity has been demonstrated in various cancer cell lines. |
| ln Vivo |
By interfering with purine metabolism, lometrexol (DDATHF; i.p. ; 15–60 mg/kg; gestation day 7.5) causes neural tube abnormalities (NTDs) and dose-dependently increases the rate of embryonic resorption and growth retardation [1]. Glycylamide ribonucleotide formyltransferase (GARFT) activity is decreased by lometrexol (ip; 40 mg/kg; gestation day 7.5) along with alterations in the levels of ATP, GTP, dATP, and dGTP [1]. Neural tube abnormalities (NTDs) are characterized by aberrant proliferation and apoptosis, which are induced by lomitrexol (ip; 40 mg/kg; gestation day 7.5) [1].
In vivo, Lometrexol has been used in clinical trials investigating lung cancer treatment, drug/formulation tissue/organ toxicity, and unspecified adult solid tumors (protocol-specific). It has anticancer activity. Its efficacy is being evaluated in various cancer types. |
| Enzyme Assay |
Lometrexol is evaluated in cell-free enzymatic assays using purified GARFT and hSHMT1/2 enzymes. The compound is incubated with the enzyme and a substrate, and the inhibition of enzyme activity is measured. IC50 values are determined to quantify the potency of inhibition.
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| Cell Assay |
Cell Viability Assay [3]
Cell Types: Mouse Leukemia L1210 Cell Tested Concentrations: 1, 30 μM Incubation Duration: 2, 4, 6, 8, 10 hrs (hours) Experimental Results: Induced 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. Lometrexol is assessed in cell-based assays using CCRF-CEM and other cancer cell lines. Cells are treated with Lometrexol, and cell proliferation, cell cycle progression, and apoptosis are measured. The compound's ability to inhibit de novo purine synthesis is evaluated by measuring the incorporation of labeled precursors into DNA and RNA. |
| Animal Protocol |
Animal/Disease Models: C57BL/6 mice (7-8 weeks, 18-20 g) [1]
Doses: 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, lasting 0, 6, 24, 48 and 96 hrs (hrs (hours)) Experimental Results: Inhibits glycylamide ribonucleotide formyltransferase (GARFT) activity, and GARFT activity is 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. Lometrexol is administered orally or intravenously in animal models and in clinical trials. It has been studied in models of lung cancer and other solid tumors. Efficacy is assessed by measuring tumor growth inhibition and survival. |
| ADME/Pharmacokinetics |
Lometrexol has a molecular weight of 443.45 and a molecular formula of C21H25N5O6. It has a CAS number of 106400-81-1. The compound is soluble in DMSO. It should be stored as a powder at -20°C for up to 3 years.
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| Toxicity/Toxicokinetics |
No detailed toxicity data is available for Lometrexol beyond its clinical trial profile. The compound is for research use only and is not intended for human therapeutic use outside of clinical trials. Its safety profile has been evaluated in clinical trials.
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| References |
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| Additional Infomation |
Lometrexol has been used in clinical trials investigating lung cancer treatment, drug/formulation tissue/organ toxicity, and unspecified adult solid tumors (protocol-specific). Lometrexol is a folic acid analogue antimetabolite with antitumor activity. As the 6R diastereomer of 5,10-diazatetrahydrofolate, Lometrexol inhibits glycamide ribonucleotide formylate transferase (GARFT), the enzyme that catalyzes the first step in the de novo purine synthesis pathway, thereby inhibiting DNA synthesis, arresting cells in the S phase of the cell cycle, and inhibiting tumor cell proliferation. This drug has been shown to be effective against tumors resistant to the folic acid antagonist methotrexate. (NCI04)
Lometrexol is also known as DDATHF and LY 264618. It is an antipurine antifolate with anticancer activity. The compound is not approved for clinical use. |
| Molecular Formula |
C21H25N5O6
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|---|---|
| Molecular Weight |
443.4531
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| Exact Mass |
443.18
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| CAS # |
106400-81-1
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| Related CAS # |
Lometrexol disodium;120408-07-3;Lometrexol hydrate;1435784-14-7;LY243246;106400-18-4
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| PubChem CID |
135413518
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| Appearance |
White to light yellow solid powder
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| Density |
1.56g/cm3
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| Index of Refraction |
1.709
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| LogP |
1.727
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
32
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| Complexity |
831
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C1[C@H](CNC2=C1C(=O)NC(=N2)N)CCC3=CC=C(C=C3)C(=O)N[C@@H](CCC(=O)O)C(=O)O
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| InChi Key |
ZUQBAQVRAURMCL-DOMZBBRYSA-N
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| InChi Code |
InChI=1S/C21H25N5O6/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)/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
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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 |
| 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 (~90.20 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.64 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), Clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 400 μL of PEG300 and mix well; then add 50 μL of Tween-80 and mix well; finally add 450 μL of physiological saline and adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.64 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), Clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of 20% SBE-β-CD saline and mix well. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (5.64 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), Clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of corn oil and mix well. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2550 mL | 11.2752 mL | 22.5505 mL | |
| 5 mM | 0.4510 mL | 2.2550 mL | 4.5101 mL | |
| 10 mM | 0.2255 mL | 1.1275 mL | 2.2550 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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