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| Targets |
GS-9219 is a nucleotide analogue prodrug that targets lymphoid cells. Upon cellular uptake, it is converted to PMEG diphosphate, which acts as an inhibitor of DNA polymerase and induces DNA chain termination, thereby inhibiting DNA synthesis and cell proliferation in actively dividing lymphocytes and hematopoietic tumor cells.
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| ln Vitro |
Rabacfosadine (GS-9219) is hydrolyzed, deaminated, and phosphorylated by enzymes in lymphocytes to produce its active metabolite, 9-(2-phosphonomethoxyethyl)guanine (PMEG) diphosphate. When it comes to hematopoietic tumor cell lines and activated lymphocytes, GS-9219 exhibits strong antiproliferative activity. It was investigated if labaksodine could stop hematopoietic tumor cells and activated lymphocytes from proliferating. According to BrdUrd incorporation, rabascofosadine inhibits the proliferation of mitogen-stimulated T and B lymphocytes with EC50 values of 135 and 42 nM, respectively. Instead of using the BrdUrd assay, the metabolism-based sodium XTT assay was used to assess rabakvorsadine in these populations in order to compare the activity of GS-9219 in dividing and non-dividing cells. The XTT assay results revealed a 127-fold difference in the rabafoxadine EC50 values between proliferating cells (EC50=135 nM) and quiescent cells (EC50=17.2 μM). Based on these findings, rabaxadine is highly selective for lymphoblastoid cells that are actively replicating [1].
GS-9219 has substantial antiproliferative activity against activated lymphocytes and hematopoietic tumor cell lines. It inhibits the proliferation of mitogen-stimulated T and B lymphocytes with EC50 values of 135 nM and 42 nM, respectively, as determined by BrdUrd incorporation. A metabolism-based XTT assay shows a 127-fold difference between EC50 values in quiescent cells (17.2 µM) and proliferating cells (135 nM), indicating substantial selectivity toward actively replicating lymphoblasts. |
| ln Vivo |
In dogs with lymphoma, rabaksodine (RAB) exhibits strong single-agent efficacy and functions differently from doxorubicin (DOX). multicenter prospective clinical trial with open label. Dogs were given doxorubicin (30 mg/m2 IV, weeks 3, 9, 15) and labavoxadine (1.0 mg/kg IV, weeks 0, 6, 12) alternately. Each month, dogs in complete remission (CR) had evaluations. Every 21 days, comprehensive assessments of the clinicopathology, response, and adverse events (AEs) were carried out. In 46 dogs who received at least one dosage of each medication, acute adverse events (AEs) that happened within 21 days following the first administration of each medicine were compared between labavoxadine and doxorubicin [2].
GS-9219 has demonstrated substantial single-agent activity in dogs with lymphoma, with a different mechanism of action than doxorubicin. In an open-label, multicenter prospective clinical trial, dogs received alternating GS-9219 (1.0 mg/kg IV) and doxorubicin, with complete responses followed by monthly evaluations. The compound exhibits selective targeting of lymphoid malignancies in vivo. |
| Enzyme Assay |
In vitro enzyme assays for GS-9219 typically involve measuring the inhibition of DNA polymerase activity by its active metabolite PMEG diphosphate. The enzyme is incubated with a DNA substrate and nucleotide precursors in the presence of varying concentrations of the compound, and DNA synthesis is quantified. Alternatively, the conversion of GS-9219 to PMEG and its diphosphate can be monitored in lymphocyte lysates using LC-MS/MS.
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| Cell Assay |
In vitro cell-based assays for GS-9219 utilize mitogen-stimulated T and B lymphocytes or hematopoietic tumor cell lines. Cells are treated with GS-9219 at various concentrations, and proliferation is measured using BrdUrd incorporation or XTT metabolism-based assays. The EC50 values are determined from dose-response curves. The selectivity index is calculated by comparing EC50 values in proliferating versus quiescent cell populations.
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| Animal Protocol |
In vivo efficacy of GS-9219 was evaluated in dogs with lymphoma using an open-label clinical trial design. Dogs received GS-9219 at 1.0 mg/kg intravenously on weeks 0, 6, and 12, alternating with doxorubicin (30 mg/m² IV) on weeks 3, 9, and 15. Complete clinicopathological evaluation and assessment of remission and adverse events were performed every 21 days.
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| ADME/Pharmacokinetics |
Pharmacokinetic data for GS-9219 indicate that as a nucleotide analogue prodrug, it is converted to PMEG in lymphocytes. The compound is designed to preferentially accumulate in lymphoid tissues. Detailed PK parameters such as half-life, Cmax, and bioavailability are not extensively reported in the available literature but are characteristic of prodrugs of acyclic nucleoside phosphonates.
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| Toxicity/Toxicokinetics |
In the canine lymphoma clinical trial, acute adverse events occurring within 21 days after administration were compared between GS-9219 and doxorubicin in 46 dogs receiving at least one dose of each agent. Specific toxicological profiles are not detailed, but as a cytotoxic nucleotide analogue, potential toxicities may include myelosuppression and gastrointestinal effects.
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| References |
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| Additional Infomation |
Rabacfosadine has been investigated for the treatment of multiple myeloma, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia. Rabacfosadine is a non-cyclic nucleotide phosphonate prodrug and polymerase inhibitor with antitumor activity that makes it a promising treatment for canine lymphoma. After administration, Rabacfosadine is hydrolyzed intracellularly to 9-(2-phosphonomethoxyethyl)-N6-cyclopropyl-2,6-diaminopurine (cPrPMEDAP), which is then deaminated to 9-(2-phosphonomethoxyethyl)guanine (PMEG) and phosphorylated to PMEG diphosphate (PMEGpp). PMEGpp binds to and inhibits DNA polymerase, thereby inhibiting DNA synthesis, leading to S-phase arrest and apoptosis. See also: Rabacfosadine succinate (active ingredient).
GS-9219 is primarily a research compound and veterinary therapeutic agent for lymphoma in dogs. It has been evaluated in clinical trials for canine lymphoma. The compound is also known as VDC-1101. It is not approved for human use. Its mechanism of action involves selective targeting of lymphoid cells through preferential conversion to the active PMEG diphosphate in lymphocytes. |
| Molecular Formula |
C21H35N8O6P
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|---|---|
| Molecular Weight |
526.53
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| Exact Mass |
526.242
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| CAS # |
859209-74-8
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| Related CAS # |
Rabacfosadine succinate;1431856-99-3
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| PubChem CID |
16047979
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
2.017
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
17
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| Heavy Atom Count |
36
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| Complexity |
760
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CCOC(=O)[C@H](C)NP(=O)(COCCN1C=NC2=C(N=C(N=C21)N)NC3CC3)N[C@@H](C)C(=O)OCC
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| InChi Key |
ANSPEDQTHURSFQ-KBPBESRZSA-N
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| InChi Code |
InChI=1S/C21H35N8O6P/c1-5-34-19(30)13(3)27-36(32,28-14(4)20(31)35-6-2)12-33-10-9-29-11-23-16-17(24-15-7-8-15)25-21(22)26-18(16)29/h11,13-15H,5-10,12H2,1-4H3,(H2,27,28,32)(H3,22,24,25,26)/t13-,14-/m0/s1
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| Chemical Name |
ethyl (2S)-2-[[2-[2-amino-6-(cyclopropylamino)purin-9-yl]ethoxymethyl-[[(2S)-1-ethoxy-1-oxopropan-2-yl]amino]phosphoryl]amino]propanoate
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| Synonyms |
GS-9219; GS9219; GS 9219
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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 : ~100 mg/mL (~189.92 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.75 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 25.0 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: ≥ 2.5 mg/mL (4.75 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 25.0 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: ≥ 2.5 mg/mL (4.75 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 | 1.8992 mL | 9.4961 mL | 18.9923 mL | |
| 5 mM | 0.3798 mL | 1.8992 mL | 3.7985 mL | |
| 10 mM | 0.1899 mL | 0.9496 mL | 1.8992 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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