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GSK-983 (GSK983) is a potent inhibitor of dihydroorotate dehydrogenase (DHODH) with antiviral activity. As an antiviral agent, it blocks RNA virus replication with EC50 values of 10–40 nM, and also blocks cell proliferation.
| Targets |
DHODH; antiviral
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|---|---|
| ln Vitro |
GSK983 (0-10000 nM; 2 h) attenuates polyomavirus SV40 in Vero cells and adenovirus 5 (Ad-5) in primary human fibroblasts (HFF) with a median effect concentration (K) of 21, respectively. Cell lines immortalized by viral infection are inhibited in growth by GSK983 (0-10000 nM; 72 h); the maximal inhibition rate (I max) is 99% and 88%, respectively. The cell lines are infected with IM9 (EBV) at nM and 7.5 nM. the MT4 (HTLV1) and B-LCL 5/2/1 (EBV) cells' median effect concentrations (K) are 7.5 nM, 16, and 14, respectively [1]. Interferon-stimulated gene expression is induced in W12, HKC cells by GSK983 (10, 100 nM; 24, 48 h) [1].
- Viral replication inhibition: 1. Broad-spectrum antiviral activity: GSK983 inhibited replication of adenovirus (Ad-5), polyomavirus (SV-40), human papillomavirus (HPV), and Epstein-Barr virus (EBV) in vitro with EC50 values of 5–20 nM. Herpes simplex virus (HSV-1), human immunodeficiency virus (HIV), and lytic EBV replication were resistant at concentrations <1 μM [1] 2. Episomal maintenance suppression: In HPV- and EBV-immortalized cells, GSK983 (10–40 nM) blocked episomal genome maintenance, leading to reduced viral gene expression [1] - Cell growth inhibition: 1. Selective cytotoxicity: GSK983 suppressed proliferation of virus-immortalized cell lines (HTLV-1, EBV, HPV, SV40, Ad-5) with EC50 values of 10–40 nM. Primary keratinocytes, fibroblasts, lymphocytes, endothelial cells, and bone marrow progenitors showed CC50 >10 μM [1] 2. Apoptosis induction: At concentrations >20 nM, GSK983 induced apoptosis in sensitive cell lines (e.g., HeLa, A549) as confirmed by caspase-3 activation and Annexin V staining [1] - Mechanism of action: 1. Interferon pathway activation: GSK983 upregulated expression of interferon-stimulated genes (ISGs) such as OAS1, MX1, and PKR in treated cells, indicating host-mediated antiviral activity [1] |
| Cell Assay |
RT-PCR[1]
Cell Types: W12, HKC cells Tested Concentrations: 10, 100 nM Incubation Duration: 24, 48 hrs (hours) Experimental Results: Induced the expression of interferon-stimulated genes in infected cells and immortalized cells, increased CSF2, IFIT1 (ISG56 ), IL6, ISG15, OAS1, OAS2, OASL, and TNFSF10 (TRAIL) gene expression. - Viral replication assay: 1. Virus infection: Cells (e.g., HEK293, Vero) were infected with viruses (MOI=0.1–1) and treated with GSK983 (0.1–10 μM) 2 hours post-infection. 2. Viral titer quantification: Supernatants were collected at 48–72 hours post-infection, and viral titers were determined by plaque assay or TCID50 [1] - Cell viability assay: 1. MTT reduction: Cells were seeded in 96-well plates (5×10³ cells/well) and treated with GSK983 (0.01–100 μM) for 72 hours. MTT solution (0.5 mg/mL) was added, and absorbance at 570 nm was measured [1] 2. Annexin V/PI staining: Treated cells were stained with Annexin V-FITC and propidium iodide, followed by flow cytometry to quantify apoptotic cells [1] |
| Toxicity/Toxicokinetics |
- In vitro toxicity:
1. Selectivity of normal cells: GSK983 showed more than 250 times higher selectivity for immortalized cells than for primary cells (CC50 ratio: 10–40 nM vs. >10 μM)[1] 2. Cell inhibition: At subapoptotic concentrations (5–10 nM), GSK983 induced G1/S phase cell cycle arrest in sensitive cell lines[1] - In vivo toxicity: No animal toxicity data were provided[1] |
| References | |
| Additional Infomation |
Research and Development Background: GSK983 is a tetrahydrocarbazole derivative. High-throughput screening revealed that it has broad-spectrum antiviral activity [1]
- Therapeutic Potential: This compound is active against oncogenic viruses (HPV, EBV) and DNA viruses (adenovirus, polyomavirus), suggesting its potential application in antiviral and tumor treatment [1] - Mechanism of Action: Unlike direct-acting antiviral drugs, GSK983 works by activating the host interferon pathway, thereby reducing the possibility of viral resistance [1] |
| Molecular Formula |
C18H16CLN3O
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|---|---|
| Molecular Weight |
325.79
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| Exact Mass |
325.098
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| Elemental Analysis |
C, 66.36; H, 4.95; Cl, 10.88; N, 12.90; O, 4.91
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| CAS # |
827591-02-6
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| PubChem CID |
11416123
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| Appearance |
White to light yellow solid powder
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| LogP |
4.598
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
23
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| Complexity |
446
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1C[C@H](C2=C(C1)C3=C(N2)C=CC(=C3)Cl)NC(=O)C4=CC=CC=N4
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| InChi Key |
WJQBOBGVBBZLJU-OAHLLOKOSA-N
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| InChi Code |
InChI=1S/C18H16ClN3O/c19-11-7-8-14-13(10-11)12-4-3-6-15(17(12)21-14)22-18(23)16-5-1-2-9-20-16/h1-2,5,7-10,15,21H,3-4,6H2,(H,22,23)/t15-/m1/s1
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| Chemical Name |
(R)-N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)picolinamide
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| Synonyms |
GSK-983; GSK983; RefChem:782742; 110-656-0; 827591-02-6; (R)-N-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)picolinamide; 2-Pyridinecarboxamide,N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-; N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]pyridine-2-carboxamide; CHEMBL551051; GSK983
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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 : ≥ 10 mg/mL (~30.69 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 | 3.0695 mL | 15.3473 mL | 30.6946 mL | |
| 5 mM | 0.6139 mL | 3.0695 mL | 6.1389 mL | |
| 10 mM | 0.3069 mL | 1.5347 mL | 3.0695 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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