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| Targets |
Toll-like receptor 4 (TLR4). GSK1795091 is a synthetic TLR4 agonist and immunologic stimulator.
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| ln Vitro |
GSK1795091 binds to and activates TLR4, thereby stimulating dendritic cells (DCs), monocytes, and macrophages. This activation results in the production of pro-inflammatory cytokines, including IFN-γ, TNF-α, IL-1β, IL-6, and IL-12. GSK1795091 demonstrates significant antitumor activity by inhibiting tumor growth and enhancing survival in murine models. The compound can be used as a vaccine adjuvant to enhance both mucosal and systemic immunity to influenza virus vaccines.
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| ln Vivo |
In order to elicit significant mucosal and systemic immune responses, GSK1795091 (CRX-601), an intranasal medication at 0.1 μg/mouse, is employed as an adjuvant in conjunction with vaccine effectiveness (H3N2) induction [1]. In mouse tumor models, GSK1795091 (25 μg/mouse; intravenously; each; once weekly for three times) slows growth and results in long-term tumors [3].
In vivo, GSK1795091 demonstrates significant antitumor activity by inhibiting tumor growth and enhancing survival in murine models. As an adjuvant combined with detergent split-influenza antigen (H3N2), it generated strong local and systemic immunity against co-administered influenza antigens while exhibiting high efficacy against heterotypic influenza challenges. Intravenously administered GSK1795091 was acceptably tolerated in healthy volunteers, had favorable PK properties, and stimulated immune cell changes in a dose-dependent manner, providing evidence of target engagement and downstream pharmacology. The compound is being evaluated in clinical trials for cancer treatment in combination with immune checkpoint inhibitors. |
| Enzyme Assay |
TLR4 activation is assessed using in vitro cell-based assays measuring NF-κB activation or cytokine production. Cells expressing TLR4 (e.g., HEK293-TLR4, THP-1 macrophages, primary human monocytes) are treated with GSK1795091 at various concentrations (typically 0.001-100 μM) and NF-κB reporter activity (luciferase) or cytokine levels (ELISA, multiplex) are measured. EC50 values are calculated from dose-response curves using nonlinear regression analysis. Selectivity is evaluated by testing against other TLR family members.
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| Cell Assay |
Cellular activity is evaluated in dendritic cells, monocytes, or macrophages. Cells are treated with GSK1795091 at various concentrations (typically 0.001-100 μM) for appropriate time periods (4-24 hours for cytokine production, 24-48 hours for differentiation/maturation). Cytokine production (IFN-γ, TNF-α, IL-1β, IL-6, IL-12) is measured by ELISA or multiplex assays from cell culture supernatants. Dendritic cell maturation markers (CD80, CD86, CD83, HLA-DR) are assessed by flow cytometry. TLR4 signaling pathway activation is confirmed by assessing NF-κB, MAPK, and IRF3 phosphorylation by Western blot.
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| Animal Protocol |
Animal/Disease Models: Female balb/c (Bagg ALBino) mouse primed with H3N2 [1]
Doses: 0.1 μg/mouse Route of Administration: Intranasal administration Experimental Results: As an adjuvant combined with detergent cleaved influenza antigen (H3N2), it can produce Robust local and systemic immunity against co-administered influenza antigens, while demonstrating high efficacy against two heterotypic influenza challenges. Mice receiving the adjuvanted vaccine had Dramatically higher IgA titers than unadjuvanted (vehicle) controls in an adjuvant dose-dependent manner. Adjuvanted vaccines promote antigen-specific IgG and IgA antibody responses and the generation of multifunctional antigen-specific Th17 cells. In vivo efficacy is studied in mouse models of cancer and influenza. GSK1795091 is administered via various routes (intravenous, subcutaneous, intranasal) at doses determined from pharmacokinetic and tolerability studies. In cancer models, tumor growth is measured by caliper twice weekly and survival is monitored. Tumor-infiltrating immune cells are assessed by flow cytometry or immunohistochemistry. In influenza models, immune responses are assessed by measuring antibody titers (ELISA), T-cell responses (ELISPOT), and protection against viral challenge. Pharmacodynamic markers include cytokine levels in serum (by ELISA or multiplex), immune cell activation markers, and target engagement markers. GSK1795091 is being evaluated in clinical trials for cancer treatment in combination with immune checkpoint inhibitors. |
| ADME/Pharmacokinetics |
GSK1795091 has a molecular formula of C57H113N3O17P and a molecular weight of 1119.5 g/mol. CAS Number: 1233589-81-5. It is a synthetic TLR4 agonist. The compound is a dendritic glycolipid TLR4 agonist with potential immunoadjuvant activity. Storage: in solvent -20°C for 3-6 months, -80°C for 12 months. Detailed pharmacokinetic parameters are available from clinical development studies.
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| Toxicity/Toxicokinetics |
Safety data for GSK1795091 are available from preclinical and clinical studies. In a first-in-human study, intravenously administered GSK1795091 was acceptably tolerated in healthy volunteers. As a TLR4 agonist, it may cause inflammatory responses including cytokine release syndrome. The compound is for research use only and has been investigated in clinical development for cancer treatment. Standard laboratory safety practices should be followed, including the use of personal protective equipment and biological safety cabinets. Consult the material safety data sheet (MSDS) for detailed safety information.
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| References |
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| Additional Infomation |
GSK1795091, a TLR4 agonist, is a Toll-like receptor 4 (TLR4) agonist with potential immunoadjuvant activity. Upon administration, GSK1795091 binds to and activates TLR4, thereby stimulating dendritic cells (DCs), monocytes, and macrophages. This activation leads to the production of pro-inflammatory cytokines, including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukins (ILs) such as IL-1β, IL-6, and IL-12. This may induce a T helper cell 1 (Th1) immune response and, when co-administered with vaccines containing tumor-associated antigens (TAAs), activate cytotoxic T lymphocyte (CTL) responses against tumor cells expressing these TAAs. TLR4 is a member of the TLR family and plays a crucial role in activating innate immunity.
GSK1795091 is a research compound and TLR4 agonist that has been investigated for clinical development in the treatment of cancer. It can be used as a vaccine adjuvant to enhance mucosal and systemic immunity to influenza virus vaccines. It is not yet approved for clinical use. Reference: Hug BA, et al. Safety, Pharmacokinetics, and Pharmacodynamics of the TLR4 Agonist GSK1795091 in Healthy Individuals: Results from a Randomized, Double-blind, Placebo-controlled, Ascending Dose Study. GSK1795091 is also known as CRX-601. The compound's ability to activate TLR4 and stimulate immune responses makes it a valuable tool for studying immunology, cancer immunotherapy, and vaccine development. |
| Molecular Formula |
C81H157N2O16P
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|---|---|
| Molecular Weight |
1446.09086871147
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| Exact Mass |
1445.127
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| CAS # |
1233589-81-5
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| PubChem CID |
25127152
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| Appearance |
White to off-white solid
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| LogP |
25.6
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
16
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| Rotatable Bond Count |
77
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| Heavy Atom Count |
100
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| Complexity |
1920
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| Defined Atom Stereocenter Count |
9
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| SMILES |
CCCCCCCCCCC[C@H](CC(=O)N[C@@H]1[C@H]([C@@H]([C@H](O[C@H]1OC[C@@H](C(=O)O)NC(=O)C[C@@H](CCCCCCCCCCC)OCCCCCCCCCC)CO)OP(=O)(O)O)OC(=O)C[C@@H](CCCCCCCCCCC)OCCCCCCCCCC)OCCCCCCCCCC
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| InChi Key |
ICLAYQQKWJGHBV-XJZMHMBSSA-N
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| InChi Code |
InChI=1S/C81H157N2O16P/c1-7-13-19-25-31-37-40-46-52-58-69(93-61-55-49-43-34-28-22-16-10-4)64-74(85)82-72(80(88)89)68-96-81-77(83-75(86)65-70(59-53-47-41-38-32-26-20-14-8-2)94-62-56-50-44-35-29-23-17-11-5)79(78(73(67-84)97-81)99-100(90,91)92)98-76(87)66-71(60-54-48-42-39-33-27-21-15-9-3)95-63-57-51-45-36-30-24-18-12-6/h69-73,77-79,81,84H,7-68H2,1-6H3,(H,82,85)(H,83,86)(H,88,89)(H2,90,91,92)/t69-,70-,71-,72+,73-,77-,78-,79-,81-/m1/s1
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| Chemical Name |
(2S)-2-[[(3R)-3-decoxytetradecanoyl]amino]-3-[(2R,3R,4R,5S,6R)-3-[[(3R)-3-decoxytetradecanoyl]amino]-4-[(3R)-3-decoxytetradecanoyl]oxy-6-(hydroxymethyl)-5-phosphonooxyoxan-2-yl]oxypropanoic acid
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| Synonyms |
GSK 1795091 GSK-1795091 GSK1795091
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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 (~17.3 mM; with ultrasonication)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (1.73 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 (1.73 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 | 0.6915 mL | 3.4576 mL | 6.9152 mL | |
| 5 mM | 0.1383 mL | 0.6915 mL | 1.3830 mL | |
| 10 mM | 0.0692 mL | 0.3458 mL | 0.6915 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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