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| Targets |
Pelitrexol targets glycinamide ribonucleotide formyltransferase (GARFT), the first folate-dependent enzyme in the de novo purine synthesis pathway. GARFT catalyzes the transfer of a formyl group from 10-formyltetrahydrofolate to glycinamide ribonucleotide (GAR), forming formylglycinamide ribonucleotide (FGAR). By inhibiting GARFT, pelitrexol blocks purine synthesis, leading to depletion of purine nucleotides and inhibition of DNA and RNA synthesis. This results in cell cycle arrest and apoptosis in rapidly proliferating cells, making pelitrexol a potential anticancer agent.
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| ln Vitro |
Pelitrexo (150 nM; 24 h) significantly suppresses mTORC1 activity in A549 cells by lowering intracellular guanine nucleotide and GTP-bound Rheb protein levels [1]. In NCI-H460 cells, pelitrexo (0-1000 mM; 16 h) dose-dependently and potently suppresses the phosphorylation levels of ribosomal protein S6 (S6RP), S6K1, and Chk1 [1]. In NCI-H460 cells, pelitrexo (100 nM; 48 h) stops the cell cycle in the G1 phase [1].
In vitro, pelitrexol inhibits the activity of glycinamide ribonucleotide formyltransferase (GARFT), the first folate-dependent enzyme of the de novo purine synthesis pathway. By blocking purine synthesis, pelitrexol depletes purine nucleotides and inhibits DNA and RNA synthesis, leading to cell cycle arrest and cell death. The compound is water-soluble and has anti-proliferative activity. In cell-based assays, pelitrexol treatment results in reduced cell proliferation and induction of apoptosis in cancer cell lines. The compound's efficacy depends on the cellular uptake via folate receptors. |
| ln Vivo |
Pelitrexo (10 mg/kg, 20 mg/kg; i.p.; every 4 days for 3 weeks) inhibits the growth of tumors and mTORC1 in mice with xenografts of non-small cell lung cancer (NSCLC) [1]. Pelitrexo (20 mg/kg; i.p.; every 4 days for 3 weeks) suppresses the function of mTORC1 and inhibits purine biosynthesis that is dependent on GARFT [1].
In vivo, pelitrexol has been studied for its potential in cancer therapy. As a GARFT inhibitor, it disrupts purine synthesis and inhibits tumor growth. The compound's water solubility and anti-proliferative activity make it a promising candidate for further development. Comprehensive in vivo efficacy studies are needed to fully characterize its therapeutic potential. Pelitrexol has been assigned a USAN (United States Adopted Name) and has been studied in clinical trials. |
| Enzyme Assay |
In vitro enzyme assays for pelitrexol involve measuring the inhibition of glycinamide ribonucleotide formyltransferase (GARFT) activity. The assay typically uses recombinant GARFT enzyme incubated with varying concentrations of pelitrexol in the presence of 10-formyltetrahydrofolate and GAR substrate. The formation of FGAR is measured using radiometric or HPLC methods. The IC₅₀ for GARFT inhibition is calculated. These assays confirm the compound's mechanism of action.
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| Cell Assay |
Cell cycle analysis[1]
Cell Types: NCI-H460 NSCLC Tested Concentrations: 100 nM Incubation Duration: 4, 8, 24, 48 hrs (hours) Experimental Results: 63% of cells accumulated in the G1 phase of the cell cycle. Cell cycle analysis[1] Cell Types: NCI-H460 NSCLC Tested Concentrations: 0, 10, 30, 100, 300, 1000 nM Incubation Duration: 16 hrs (hours) Experimental Results: Inhibition of p-S6RP, p-S6K1 and p-Chk1 levels. In vitro cell-based assays for pelitrexol evaluate its effects on cancer cell proliferation and survival. Cancer cells are cultured in appropriate media and treated with serial dilutions of pelitrexol. Cell proliferation is assessed using MTT, BrdU incorporation, or cell counting assays. Cell cycle analysis is performed using propidium iodide staining and flow cytometry. Apoptosis is quantified by measuring caspase-3/7 activity or by Annexin V staining. These assays confirm the compound's anti-proliferative activity. |
| Animal Protocol |
Animal/Disease Models: Mouse non-small cell lung cancer (NSCLC) xenograft model [1]
Doses: 10 mg/kg, 20 mg/kg Route of Administration: intraperitoneal (ip) injection; Group 1 once every 4 days for 3 weeks; Group 2 The results of administration on days 1, 4, and 7 of each group: In group 1, 10 mg/kg and 20 mg/kg inhibited tumor growth by 64% and 69%, respectively. Inhibits mTORC1-dependent phosphorylation of S6K1, S6RP and CAD Group 2 20 mg/kg. In vivo animal experiments for pelitrexol have been conducted in mouse xenograft models of cancer. Tumor-bearing mice are treated with pelitrexol via various routes of administration. Tumor growth is monitored by caliper measurements, and tumor growth inhibition is calculated. Pharmacodynamic endpoints include assessment of purine nucleotide levels in tumor tissues. Pharmacokinetic studies are conducted to determine the compound's half-life, clearance, and tissue distribution. Comprehensive in vivo studies are needed. |
| ADME/Pharmacokinetics |
Pharmacokinetic (PK) data for pelitrexol are available from preclinical and clinical studies. The compound has a molecular weight of 463.51 g/mol and is water-soluble. As a folate analog, pelitrexol is taken up by cells via folate receptors. The compound's half-life, bioavailability, and excretion profile have been characterized in the context of its clinical development. Comprehensive PK data are available from pharmaceutical studies.
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| Toxicity/Toxicokinetics |
The toxicity profile of pelitrexol has been evaluated in preclinical and clinical studies. As an antifolate that inhibits purine synthesis, the compound may have effects on rapidly dividing normal tissues, such as bone marrow and gastrointestinal epithelium. Common side effects may include myelosuppression and gastrointestinal toxicity. The compound should be used under medical supervision. Comprehensive toxicological studies are available from clinical development.
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| References | |
| Additional Infomation |
Pelitrexol has been used in clinical trials investigating its application in the treatment of unspecified types of adult solid tumors under specific regimens. Pelitrexol is a water-soluble antifolate drug with antiproliferative activity. Pelitrexol inhibits the activity of glycamide ribonucleotide formylate transferase (GARFT), the first folate-dependent enzyme in the de novo purine synthesis pathway, which is crucial for cell proliferation. Enzyme inhibition reduces the pool of purine nucleotides required for DNA replication and RNA transcription. Therefore, the drug causes cell cycle arrest in the S phase, ultimately inhibiting tumor cell proliferation.
Pelitrexol is a water-soluble antifolate with anti-proliferative activity that functions as a glycinamide ribonucleotide formyltransferase (GARFT) inhibitor. It has a molecular formula of C₂₀H₂₅N₅O₆S and a molecular weight of 463.51 g/mol. Pelitrexol inhibits the first folate-dependent enzyme of the de novo purine synthesis pathway, blocking purine synthesis and inhibiting DNA and RNA synthesis. The compound has been studied for its potential in cancer therapy and has been assigned a USAN. |
| Molecular Formula |
C20H25N5O6S
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|---|---|
| Molecular Weight |
463.5074
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| Exact Mass |
463.152
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| CAS # |
446022-33-9
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| PubChem CID |
135431074
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.6±0.1 g/cm3
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| Index of Refraction |
1.743
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| LogP |
-0.58
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
32
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| Complexity |
859
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CC1=C(SC(=C1)C(=O)N[C@@H](CCC(=O)O)C(=O)O)CC[C@H]2CC3=C(NC2)N=C(NC3=O)N
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| InChi Key |
QXOPTIPQEVJERB-JQWIXIFHSA-N
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| InChi Code |
InChI=1S/C20H25N5O6S/c1-9-6-14(18(29)23-12(19(30)31)3-5-15(26)27)32-13(9)4-2-10-7-11-16(22-8-10)24-20(21)25-17(11)28/h6,10,12H,2-5,7-8H2,1H3,(H,23,29)(H,26,27)(H,30,31)(H4,21,22,24,25,28)/t10-,12-/m0/s1
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| Chemical Name |
(2S)-2-[[5-[2-[(6S)-2-amino-4-oxo-5,6,7,8-tetrahydro-3H-pyrido[2,3-d]pyrimidin-6-yl]ethyl]-4-methylthiophene-2-carbonyl]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 : ~25 mg/mL (~53.94 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.49 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 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 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to 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: ≥ 2.08 mg/mL (4.49 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 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.49 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1575 mL | 10.7873 mL | 21.5745 mL | |
| 5 mM | 0.4315 mL | 2.1575 mL | 4.3149 mL | |
| 10 mM | 0.2157 mL | 1.0787 mL | 2.1575 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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