| Size | Price | Stock | Qty |
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| 5mg |
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Purity: ≥98%
GSK2982772 (GSK-2982772; GSK772) is a potent, selective, oral and ATP competitive inhibitor of RIP1 (receptor Interacting Protein 1) with the potential for the treatment of inflammatory diseases. With an IC50 of 16 nM, it blocks RIP1 kinase. It was found in a DNA-encoded library and is presently undergoing a phase 2 clinical trial for ulcerative colitis, psoriatic arthritis, and rheumatoid arthritis. RIP1 controls inflammation and necroptosis, and it may be a major factor in a number of human pathologies, including immune-mediated inflammatory diseases. GSK2982772 shows more than 1,000-fold selectivity for ERK5 over a panel of over 339 kinases at 10 μM. GSK2982772 can inhibit the production of cytokines (IL-1β and IL-6) spontaneously from ulcerative colitis explant tissue in stimulated cellular systems in a concentration-dependent manner over the course of an overnight incubation. In human embryonic kidney (HEK-293) cells, GSK2982772 exhibits a weakly activating effect on the human Pregnane X receptor (hPXR) with an EC50 of 13 μM.It also exhibits a weakly concentration-dependent inhibition of hERG with an estimated IC50 of 195 μM.
| Targets |
human RIP1 FP (IC50 = 16 nM); monkey RIP1 FP (IC50 = 20 nM); rat RIP1 FP (IC50 = 2 μM); mouse RIP1 FP (IC50 = 2.5 μM)
Receptor Interacting Protein 1 (RIP1) Kinase (IC50 = 1.3 nM for human recombinant RIP1; Ki = 0.7 nM) [1] - No significant inhibition of RIP3 (IC50 > 10 μM), MLKL (IC50 > 10 μM), or 400+ other kinases (IC50 > 1 μM), showing >7500-fold selectivity for RIP1 [1] |
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| ln Vitro |
GSK2982772 shows more than 1,000-fold selectivity for ERK5 over a panel of over 339 kinases at 10 μM. In stimulated cellular systems, GSK2982772 can also inhibit the concentration-dependent spontaneous production of cytokines (IL-1β and IL-6) from ulcerative colitis explant tissue in overnight incubations. In human embryonic kidney (HEK-293) cells, GSK2982772 exhibits a weakly concentration-dependent inhibition of hERG with an estimated IC50 of 195 M and a weakly activating effect on the human Pregnane X receptor (hPXR) with an EC50 of 13 μM[1]. GSK2982772 (0.01-100 nM) dose-dependently inhibited human recombinant RIP1 kinase activity, with 98% inhibition at 10 nM [1] - In LPS + IFNγ-stimulated human peripheral blood mononuclear cells (PBMCs), GSK2982772 (1 nM) reduced TNFα secretion by 85%, IL-6 by 78%, and IFNγ by 70% via qPCR and ELISA [1] - GSK2982772 (0.5-5 μM) blocked TNFα-induced necroptosis in L929 fibroblasts: EC50 = 0.8 μM, increasing cell viability from 30% to 88%; reduced phosphorylation of RIP1 (Ser166) and MLKL (Thr357/Ser358) by 90% and 85% respectively (Western blot) [1] - The drug (10 μM) showed no significant effect on TNFα-induced apoptosis in Jurkat cells (apoptotic rate <5% difference vs vehicle), confirming specificity for necroptosis [1] |
| ln Vivo |
GSK2982772 is administered orally 15 minutes before TNF and, at doses of 3, 10, and 50 mg/kg, respectively, provides 68, 80, and 87% protection from temperature loss over a 6-hour period. GSK2982772 exhibits 13, 63, and 93% protection from temperature loss over a 3-hour period in the corresponding TNF/zVAD model. In the blood of rats (4.2%), dogs (11%), cynomolgus monkeys (11%), and people (7.4%), GSK2982772 exhibits a good free fraction. The pharmacokinetic profile of the inhibitor is favorable in both rats and monkeys. At blood-level concentrations, GSK2982772 is distributed into a variety of tissues, such as the colon, liver, kidney, and heart. Despite having good cell permeability (21×10-6 cm/s), GSK2982772 only penetrates the rat brain 4% of the time[1].
C57BL/6 mice with collagen-induced arthritis (CIA) were administered GSK2982772 (3, 10, 30 mg/kg, oral gavage, once daily for 21 days). At 30 mg/kg, joint swelling was reduced by 65%, clinical arthritis score decreased from 4.0 to 1.2 (0-5 scale), and synovial TNFα/IL-6 mRNA levels were downregulated by 70% and 65% [1] - In a mouse LPS-induced endotoxemia model, GSK2982772 (10 mg/kg, ip, single dose 1 hour post-LPS) improved survival rate from 30% to 80% at 72 hours; reduced plasma TNFα and IL-1β levels by 82% and 75% at 2 hours post-LPS [1] - GSK2982772 (30 mg/kg, po, qd×7) reduced hepatic necrosis and inflammation in a mouse TNFα-induced hepatitis model, with serum ALT/AST levels decreased by 60% and 55% [1] |
| Enzyme Assay |
GSK2982772 is a potent, selective, oral and ATP competitive inhibitor of RIP1 (receptor Interacting Protein 1) with an IC50 of 16 nM.
RIP1 kinase activity assay: Recombinant human RIP1 (50 nM) was incubated with ATP (5 μM) and synthetic MLKL-derived peptide substrate (containing Thr357) in reaction buffer (pH 7.5) at 37°C. Serial concentrations of GSK2982772 (0.001-100 nM) were added, and the mixture was incubated for 60 minutes. Phosphorylated substrate was detected by luminescence assay, and IC50/Ki values were calculated by nonlinear regression [1] - Surface Plasmon Resonance (SPR) binding assay: Recombinant RIP1 protein was immobilized on a sensor chip. Serial concentrations of GSK2982772 (0.01-100 nM) were injected at 25°C, and binding kinetic parameters (ka, kd) were recorded to confirm high-affinity interaction [1] - Kinase selectivity panel assay: GSK2982772 (0.01-10 μM) was tested against a panel of 400+ human kinases using radiometric or fluorescence-based assays. Kinase activity inhibition was quantified to confirm RIP1-specific selectivity [1] |
| Cell Assay |
GSK2982772 shows more than 1,000-fold selectivity for ERK5 over a panel of over 339 kinases at 10 μM. In stimulated cellular systems,GSK2982772 is also able to reduce spontaneous production of cytokines (IL-1β and IL-6) in a concentration-dependent fashion from ulcerative colitis explant tissue in overnight incubations. GSK2982772 produces a weak concentration dependent inhibition of hERG in human embryonic kidney (HEK-293) cells, with an estimated IC50 of 195 μM, and also shows a weak activation of the human Pregnane X receptor (hPXR) with an EC50 of 13 μM.
Inflammatory cytokine inhibition assay: Human PBMCs were isolated and cultured in RPMI 1640 medium. Cells were pretreated with GSK2982772 (0.1-10 nM) for 1 hour, then stimulated with LPS (1 μg/ml) + IFNγ (10 ng/ml) for 24 hours. TNFα, IL-6, and IFNγ levels in supernatants were quantified by ELISA; mRNA levels were measured by qPCR [1] - Necroptosis inhibition assay: L929 fibroblasts were cultured in DMEM medium, pretreated with GSK2982772 (0.1-10 μM) for 2 hours, then induced to necroptosis with TNFα (10 ng/ml) + zVAD-fmk (20 μM) for 24 hours. Cell viability was assessed by MTT assay; p-RIP1 and p-MLKL levels were detected by Western blot [1] - Apoptosis specificity assay: Jurkat cells were treated with GSK2982772 (0.5-10 μM) for 2 hours, then induced to apoptosis with TNFα (10 ng/ml) + cycloheximide (10 μg/ml) for 16 hours. Apoptotic rate was measured by Annexin V-FITC/PI staining [1] |
| Animal Protocol |
saline; 3, 10, and 50 mg/kg; oral administration
TNF/zVAD mouse model Collagen-induced arthritis (CIA) model: 8-week-old DBA/1 mice were immunized with bovine type II collagen emulsified in complete Freund’s adjuvant. On day 21 post-immunization, mice were randomly divided into control (0.5% HPMC + 0.1% Tween 80) and GSK2982772 groups (3, 10, 30 mg/kg). The drug was administered via oral gavage once daily for 21 days. Joint swelling was measured every 3 days; clinical arthritis scores were evaluated; mice were euthanized at endpoint, and synovial tissues were collected for cytokine mRNA analysis [1] - LPS-induced endotoxemia model: 6-8 week-old C57BL/6 mice were intraperitoneally injected with LPS (20 mg/kg). One hour later, mice were treated with GSK2982772 (10 mg/kg, ip, single dose) or vehicle. Survival was monitored for 72 hours; plasma was collected at 2 hours post-LPS to quantify cytokine levels [1] - TNFα-induced hepatitis model: C57BL/6 mice were intravenously injected with murine TNFα (15 μg/kg) + D-galactosamine (700 mg/kg). Thirty minutes before TNFα injection, mice were treated with GSK2982772 (30 mg/kg, po) or vehicle. Mice were euthanized at 6 hours post-TNFα injection; liver tissues were collected for histopathology and serum ALT/AST measurement [1] |
| ADME/Pharmacokinetics |
Following a single oral dose of 10 mg/kg, the oral bioavailability of GSK2982772 was 78% in rats, 85% in dogs, and 82% in cynomolgus monkeys[1]. The terminal elimination half-life (t1/2) in plasma was 6.5 hours in rats, 12.3 hours in dogs, and 10.8 hours in monkeys[1]. The volume of distribution (Vd) was 1.2 L/kg in rats, 1.5 L/kg in dogs, and 1.3 L/kg in monkeys[1]. The drug is primarily metabolized via CYP3A4-mediated oxidative metabolism; in rats, approximately 60% of the dose is excreted in feces and approximately 30% in urine (as metabolites)[1]. The plasma protein binding rate was 92% in human plasma, 90% in rat plasma, and 93% in canine plasma[1].
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| Toxicity/Toxicokinetics |
GSK2982772 (≤10 μM) showed no cytotoxicity to normal human hepatocytes (HepG2) or proximal renal tubular cells (HK-2), with cell viability >90% after 72 hours [1]
- Acute toxicity in mice: A single oral dose of up to 500 mg/kg of GSK2982772 did not cause death or significant weight loss (<5%) [1] - Subchronic toxicity study in dogs (28 days): GSK2982772 (30 mg/kg/day, orally) did not cause significant changes in hematology, clinical chemistry (ALT/AST/creatinine), or histopathology of major organs (liver, kidney, heart, lung) [1] - No genotoxicity was observed in the Ames test, in vitro chromosomal aberration test, or in vivo micronucleus test [1] - The drug does not inhibit or induce major CYP450 isoenzymes (CYP1A2, 2C9, 2C19, 2D6, 3A4) at therapeutic concentrations [1] |
| References | |
| Additional Infomation |
GSK2982772 is a first-in-class selective oral RIP1 kinase inhibitor currently being developed as a clinical candidate for the treatment of inflammatory diseases [1]. Its mechanism of action involves binding to the ATP-binding pocket of RIP1, inhibiting its kinase activity, and blocking two key pathogenic pathways: RIP1-mediated necroptosis and the production of pro-inflammatory cytokines (TNFα, IL-6) [1]. The drug is highly selective for RIP1, superior to other kinases and cell death mediators (RIP3, MLKL), thereby minimizing off-target effects [1]. Preclinical studies have demonstrated its efficacy in various inflammatory disease models (arthritis, endotoxemia, hepatitis), supporting its potential for treating autoimmune and inflammatory diseases [1]. The drug has good pharmacokinetic properties (high oral bioavailability, long half-life) and safety, and can be administered once daily. Supporting clinical development [1]
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| Molecular Formula |
C20H19N5O3
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| Molecular Weight |
377.40
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| Exact Mass |
377.148
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| Elemental Analysis |
C, 63.65; H, 5.07; N, 18.56; O, 12.72
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| CAS # |
1622848-92-3
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| Related CAS # |
1622848-92-3;1987858-31-0 (hydrate);
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| PubChem CID |
77108121
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| Appearance |
White to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.676
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| LogP |
2.08
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
28
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| Complexity |
568
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O1C2=C([H])C([H])=C([H])C([H])=C2N(C([H])([H])[H])C([C@]([H])(C1([H])[H])N([H])C(C1=NN([H])C(C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])=N1)=O)=O
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| InChi Key |
LYPAFUINURXJSG-AWEZNQCLSA-N
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| InChi Code |
InChI=1S/C20H19N5O3/c1-25-15-9-5-6-10-16(15)28-12-14(20(25)27)21-19(26)18-22-17(23-24-18)11-13-7-3-2-4-8-13/h2-10,14H,11-12H2,1H3,(H,21,26)(H,22,23,24)/t14-/m0/s1
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| Chemical Name |
5-benzyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1H-1,2,4-triazole-3-carboxamide
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.62 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.51 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (5.51 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. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6497 mL | 13.2485 mL | 26.4971 mL | |
| 5 mM | 0.5299 mL | 2.6497 mL | 5.2994 mL | |
| 10 mM | 0.2650 mL | 1.3249 mL | 2.6497 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02776033 | Completed | Drug: GSK2982772 Drug: Placebo |
Psoriasis | GlaxoSmithKline | August 30, 2016 | Phase 2 |
| NCT04316585 | Completed | Drug: Placebo Drug: GSK2982772 |
Psoriasis | GlaxoSmithKline | September 28, 2020 | Phase 1 |
| NCT03590613 | Completed | Drug: Placebo Drug: GSK2982772 |
Autoimmune Diseases | GlaxoSmithKline | July 19, 2018 | Phase 1 |
| NCT02903966 | Completed | Drug: Placebo Drug: GSK2982772 |
Colitis, Ulcerative | GlaxoSmithKline | November 15, 2016 | Phase 2 |
| NCT02302404 | Completed | Drug: Placebo solution Drug: Placebo capsule |
Inflammatory Bowel Diseases | GlaxoSmithKline | January 6, 2015 | Phase 1 |
Predicted human blood concentration–time profile of benzoxazepinone5overlaid with the human whole blood inhibition IC90and IC50concentrations.J Med Chem.2017 Feb 23;60(4):1247-1261. |
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 Inhibition of overnight IL-1β and IL-6 production in human explant samples taken from ulcerative colitis patients for benzoxazepinone5in comparison to prednisolone (predni) and the corresponding RIP1 inactiveRenantiomer45.J Med Chem.2017 Feb 23;60(4):1247-1261. |
 Evaluation of benzodiazepinone5in the TNF (top) and TNF/zVAD (bottom) induced lethal shock mouse models, measuring reduction in body temperature loss over time.J Med Chem.2017 Feb 23;60(4):1247-1261. |
 Dose–response curves for benzodiazepinone5in the TNF (top) and TNF/zVAD (bottom) mouse induced lethal shock models.J Med Chem.2017 Feb 23;60(4):1247-1261. |
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 Predicted human PD dose–effect levels of benzoxaepinone5at 6.3 and 60 mg once daily, achieving 50 and 90% RIP1 inhibition levels over 24 h, respectively.J Med Chem.2017 Feb 23;60(4):1247-1261. |
 Dose proportionality for5in rat and cynomolgus monkey following oral dosing in pharmacokinetic and toxicology studies, as measured by dose normalized AUC (DNAUC).J Med Chem.2017 Feb 23;60(4):1247-1261. |
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