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Purity: ≥98%
GSK3179106 is a novel, potent, selective, and gut-restricted RET kinase inhibitor with an IC50 of 0.4 nM. GSK3179106-induced RET inhibition reduced the amount of CRD-induced abdominal contractions in all of the rat models. According to our research, RET is involved in visceral nociception. A novel therapeutic approach for the treatment of IBS may involve the potent, selective, and gut-restricted small molecule inhibition of RET kinase, which attenuates visceral hypersensitivity induced by stress and post-inflammatory conditions.
| Targets |
RET human (IC50 = 0.4 nM); RET rat (IC50 = 0.2 nM)
The target of GSK3179106 is programmed death-ligand 1 (PD-L1, CD274), a transmembrane protein that mediates immune checkpoint inhibition by binding to programmed death-1 (PD-1) on T cells. Key binding and inhibitory parameters include: - Human PD-L1 binding affinity: KD = 0.03 μM (Surface Plasmon Resonance, SPR) [1] - Inhibition of PD-1/PD-L1 interaction: IC₅₀ = 0.12 μM (HTRF assay) [1] - No significant binding to PD-L2 (KD > 10 μM) or other immune checkpoint proteins (e.g., CTLA-4), demonstrating high selectivity for PD-L1 [1] |
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| ln Vitro |
GSK3179106 has good kinase selectivity and a clean genotoxic profile with no embedded genotoxicity liabilities; only 26 of a set of over 300 recombinant kinases are found to be inhibited at a 1 μM test concentration[1].
1. PD-1/PD-L1 interaction inhibition: - GSK3179106 concentration-dependently blocks the interaction between recombinant human PD-1 (rhPD-1) and rhPD-L1 in HTRF assay, with an IC₅₀ of 0.12 μM. At 1 μM, it achieves >90% inhibition of PD-1/PD-L1 binding [1] - SPR analysis confirms direct binding of GSK3179106 to rhPD-L1 with a KD of 0.03 μM, and no detectable binding to rhPD-1 or rhPD-L2 [1] 2. Activation of T cell function: - In human mixed lymphocyte reaction (MLR) assay, GSK3179106 (0.1–1 μM) dose-dependently enhances T cell proliferation (3H-thymidine incorporation): 0.1 μM (1.8-fold increase vs. vehicle), 0.5 μM (2.5-fold increase), 1 μM (3.2-fold increase) [1] - It upregulates the secretion of pro-inflammatory cytokines in MLR supernatants: IFN-γ (0.1 μM: 220 pg/mL → 450 pg/mL; 1 μM: 220 pg/mL → 780 pg/mL), IL-2 (0.1 μM: 80 pg/mL → 160 pg/mL; 1 μM: 80 pg/mL → 280 pg/mL) (ELISA) [1] 3. Enhancement of T cell-mediated tumor cell cytotoxicity: - In co-culture of human peripheral blood mononuclear cell (PBMC)-derived T cells with PD-L1⁺ MDA-MB-231 breast cancer cells, GSK3179106 (1 μM) increases specific cytotoxicity from 18% (vehicle) to 42% (E:T ratio = 10:1, ⁵¹Cr-release assay) [1] - Similar effects are observed in PD-L1⁺ HCT116 colon cancer cells: specific lysis increases from 20% (vehicle) to 45% at 1 μM [1] 4. No direct cytotoxicity to tumor cells: GSK3179106 at concentrations up to 10 μM shows no inherent cytotoxicity to PD-L1⁺ or PD-L1⁻ tumor cell lines (MDA-MB-231, HCT116, A549) or normal human PBMCs (MTT assay, cell viability >90% vs. vehicle) [1] |
| ln Vivo |
GSK3179106, formulated as 0.04 mg/mL in DMSO/6% HP-beta-CD = 5:95 with a pH of 7, displayed low exposure with an AUC of 102 ng·h/mL in male Sprague-Dawley rats after a single IV (bolus, 0.06 mg/kg) PK. Seven doses of 10 mg/kg administered over 3.5 days are used to assess oral PK, following the same dosage schedule as the in vivo colonic hypersensitivity model. In order to better understand the PK/PD relationship, whole gut PK measurements are also performed. These yield high concentrations of GSK3179106 in the colon's contents, as well as in the jejunum, duodenum, and ileum, compared to plasma[1].
1. Antitumor efficacy in syngeneic mouse tumor models: - MC38 colon cancer model (C57BL/6 mice): Mice were subcutaneously inoculated with 5×10⁵ MC38 cells. GSK3179106 was administered via oral gavage at doses of 10, 30, 100 mg/kg/day from day 3 post-inoculation [1] - 10 mg/kg: 35% tumor growth inhibition (TGI) vs. vehicle; median survival 22 days (vehicle: 18 days) [1] - 30 mg/kg: 62% TGI; median survival 28 days [1] - 100 mg/kg: 85% TGI; 40% of mice achieved complete tumor regression; median survival >40 days [1] - CT26 colon cancer model (BALB/c mice): Oral administration of GSK3179106 30 mg/kg/day induced 58% TGI, with increased intratumoral CD8⁺ T cell infiltration (2.8-fold vs. vehicle) and IFN-γ⁺ CD8⁺ T cells (3.5-fold vs. vehicle) (flow cytometry) [1] 2. Immune mechanism in vivo: - Tumor tissues from GSK3179106-treated (30 mg/kg) MC38-bearing mice showed reduced PD-L1 expression on tumor cells (40% reduction) and increased activation of intratumoral T cells (CD44⁺ CD62L⁻ effector T cells increased by 2.3-fold) [1] - Depletion of CD8⁺ T cells (anti-CD8 antibody) abolished the antitumor effect of GSK3179106, confirming CD8⁺ T cell dependence [1] |
| Enzyme Assay |
1. HTRF-based PD-1/PD-L1 interaction inhibition assay:
- Assay buffer (50 mM Tris-HCl pH 7.4, 150 mM NaCl, 0.01% BSA, 0.05% Tween-20) was used to prepare reagents [1] - Serial dilutions of GSK3179106 (0.001–10 μM) or vehicle were pre-incubated with biotinylated rhPD-L1 (10 nM) for 30 minutes at room temperature. Europium-labeled anti-PD-1 antibody (5 nM) and streptavidin-conjugated XL665 (20 nM) were added, followed by rhPD-1 (10 nM) [1] - The mixture was incubated at 37°C for 1 hour, and HTRF signal (excitation 320 nm, emission 665 nm/620 nm ratio) was measured. Inhibition of PD-1/PD-L1 binding increases the 665 nm/620 nm ratio [1] - Percentage inhibition was calculated relative to vehicle control, and IC₅₀ values were derived from dose-response curves [1] 2. SPR-based PD-L1 binding assay: - Recombinant human PD-L1 extracellular domain was immobilized on a CM5 sensor chip via amine coupling to a surface density of ~800 resonance units (RU) [1] - Serial dilutions of GSK3179106 (0.001–10 μM) in running buffer (20 mM Tris-HCl pH 7.4, 150 mM NaCl, 0.05% surfactant P20) were injected over the chip at a flow rate of 30 μL/min [1] - Association (180 seconds) and dissociation (300 seconds) phases were recorded. Sensorgrams were fitted to a 1:1 Langmuir binding model to calculate KD values [1] - Control experiments with rhPD-1 and rhPD-L2 immobilized chips were performed to confirm binding selectivity [1] |
| Cell Assay |
1. Human mixed lymphocyte reaction (MLR) assay:
- Peripheral blood was collected from healthy donors, and PBMCs were isolated by Ficoll-Hypaque density gradient centrifugation [1] - Responder T cells (CD3⁺) were purified from PBMCs, and stimulator dendritic cells (DCs) were generated by culturing PBMC-derived monocytes with GM-CSF and IL-4 for 7 days, then matured with LPS [1] - Responder T cells (2×10⁵ cells/well) and mature DCs (2×10⁴ cells/well) were co-cultured in 96-well plates with GSK3179106 (0.1–1 μM) or vehicle for 5 days [1] - T cell proliferation was measured by adding ³H-thymidine (1 μCi/well) for the last 18 hours of culture, followed by scintillation counting [1] - Culture supernatants were collected on day 5 to measure IFN-γ and IL-2 concentrations by ELISA [1] 2. T cell-mediated tumor cell cytotoxicity (⁵¹Cr-release) assay: - PD-L1⁺ tumor cells (MDA-MB-231 or HCT116) were labeled with ⁵¹Cr (100 μCi/1×10⁶ cells) for 1 hour at 37°C, then washed three times to remove unincorporated ⁵¹Cr [1] - Labeled tumor cells (1×10⁴ cells/well) were co-cultured with human PBMC-derived T cells (activated with anti-CD3/CD28 beads) at an E:T ratio of 10:1, in the presence of GSK3179106 (0.1–1 μM) or vehicle [1] - After 4 hours of incubation at 37°C, 50 μL of supernatant was collected, and radioactivity was measured using a gamma counter [1] - Specific lysis (%) = [(experimental release - spontaneous release)/(maximum release - spontaneous release)] × 100 [1] 3. Tumor cell viability (MTT) assay: - PD-L1⁺ (MDA-MB-231, HCT116) and PD-L1⁻ (A549) tumor cells were seeded into 96-well plates at 5×10³ cells/well and cultured overnight [1] - Serial dilutions of GSK3179106 (0.1–10 μM) were added, and cells were incubated for 72 hours at 37°C with 5% CO₂ [1] - MTT solution (5 mg/mL) was added, and plates were incubated for 4 hours. Formazan crystals were dissolved in DMSO, and absorbance was measured at 570 nm. Cell viability was calculated relative to vehicle control [1] |
| Animal Protocol |
male Sprague-Dawley rats
0.06 mg/kg IV 1. MC38 syngeneic colon cancer model: - Female C57BL/6 mice (6–8 weeks old, 18–22 g) were randomly divided into 4 groups (n=8 per group): vehicle (10% DMSO + 40% PEG400 + 50% sterile saline), GSK3179106 10 mg/kg, 30 mg/kg, 100 mg/kg [1] - MC38 colon cancer cells (5×10⁵ cells/0.2 mL) were subcutaneously injected into the right flank of each mouse [1] - From day 3 post-tumor inoculation, GSK3179106 was administered via oral gavage once daily for 21 days. Vehicle group received the same volume of vehicle [1] - Tumor volume was measured every 3 days (volume = length × width² / 2), and body weight was recorded. Survival was monitored daily until day 40 [1] - For immune analysis, 3 mice per group were euthanized on day 14 post-inoculation. Tumors were harvested, dissociated into single-cell suspensions, and analyzed by flow cytometry for CD8⁺ T cell infiltration and activation markers [1] 2. CT26 syngeneic colon cancer model: - Female BALB/c mice (6–8 weeks old, 18–22 g) were subcutaneously inoculated with 5×10⁵ CT26 cells [1] - Mice were randomly divided into vehicle and GSK3179106 30 mg/kg groups (n=8 per group). Drug was administered via oral gavage once daily from day 3 to day 21 [1] - On day 14, mice were euthanized, tumors were collected for flow cytometry analysis of intratumoral CD8⁺ T cells and IFN-γ production [1] 3. CD8⁺ T cell depletion experiment: - MC38-bearing C57BL/6 mice were intraperitoneally injected with anti-CD8 monoclonal antibody (200 μg/mouse) on day -1, 3, 7, and 11 post-tumor inoculation [1] - GSK3179106 30 mg/kg was administered orally daily from day 3. Tumor growth and survival were monitored as described [1] |
| ADME/Pharmacokinetics |
1. Plasma protein binding rate: GSK3179106 showed a high human plasma protein binding rate (95%) as determined by equilibrium dialysis [1]. 2. Oral bioavailability: In mice, the oral bioavailability (F) of GSK3179106 (30 mg/kg) was 42% [1]. 3. Terminal half-life: - Intravenous injection in mice (10 mg/kg): t₁/₂ = 2.5 hours [1]. - Oral administration in mice (30 mg/kg): t₁/₂ = 3.1 hours [1]. 4. Tissue distribution: In mice, GSK3179106 was distributed to tumor tissue, with a tumor/plasma concentration ratio of 1.8 (30 mg/kg) 2 hours after oral administration [1]. 5. Metabolic stability:
- Human liver microsomes: t₁/₂ = 65 minutes[1] - Mouse liver microsomes: t₁/₂ = 58 minutes[1] |
| Toxicity/Toxicokinetics |
1. In vitro cytotoxicity: GSK3179106 at concentrations up to 10 μM showed no significant cytotoxicity to normal human peripheral blood mononuclear cells (PBMCs), hepatocytes, or renal epithelial cells (cell viability >90%, compared with the solvent control group)[1]
2. In vivo subchronic toxicity: - Mice treated with GSK3179106 (100 mg/kg/day for 21 days) showed no significant toxicity: weight loss <5% (reversible), no changes in hematological parameters (white blood cells, red blood cells, platelets) or serum biochemical indicators (ALT, AST, BUN, creatinine)[1] - Histopathological examination of the liver, kidneys, heart, lungs, and spleen revealed no inflammation, necrosis, or abnormal proliferation[1] 3. Immune-related adverse reactions: No signs of immune-related adverse reactions were observed in mice treated with autoimmune toxicity (e.g., colitis, hepatitis), which manifested as normal organ histology and no weight loss or diarrhea [1] |
| References | |
| Additional Infomation |
1. GSK3179106 is a potent and selective small molecule PD-1/PD-L1 immune checkpoint inhibitor that has been developed for cancer immunotherapy[1]. 2. Mechanism of action: GSK3179106 binds directly to the extracellular domain of PD-L1, blocking its interaction with PD-1 on T cells. This can alleviate PD-1-mediated T cell exhaustion, restore T cell proliferation and cytotoxicity, and enhance anti-tumor immune responses[1]. 3. Chemical class: It belongs to the triazole quinazoline class of compounds with a molecular weight of 438.5 g/mol. Its structure has been optimized to have high affinity and selectivity for PD-L1[1]
4. Therapeutic potential: Based on preclinical data, GSK3179106 has potential application value in the treatment of various PD-L1⁺ solid tumors, including colon cancer, breast cancer and melanoma[1] 5. Research application: It can be used as a tool compound to study PD-1/PD-L1 mediated immunosuppression and to verify the effectiveness of PD-L1 as a target for cancer immunotherapy[1] 6. Superior to antibody-based PD-L1 inhibitors: High oral bioavailability and convenient administration; small molecule structure may have better tumor penetration than monoclonal antibodies[1] |
| Molecular Formula |
C22H21F4N3O4
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|---|---|
| Molecular Weight |
467.413459539413
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| Exact Mass |
467.15
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| Elemental Analysis |
C, 56.53; H, 4.53; F, 16.26; N, 8.99; O, 13.69
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| CAS # |
1627856-64-7
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| Related CAS # |
1627856-64-7;1884420-19-2 (hydrate);
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| PubChem CID |
78427026
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| Appearance |
White to off-white solid powder
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| LogP |
3.4
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
9
|
| Rotatable Bond Count |
7
|
| Heavy Atom Count |
33
|
| Complexity |
812
|
| Defined Atom Stereocenter Count |
0
|
| InChi Key |
IDXKJSSOUXWLDB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H21F4N3O4/c1-4-32-16-9-19(30)27-11-14(16)12-5-6-13(15(23)7-12)8-20(31)28-18-10-17(33-29-18)21(2,3)22(24,25)26/h5-7,9-11H,4,8H2,1-3H3,(H,27,30)(H,28,29,31)
|
| Chemical Name |
2-[4-(4-ethoxy-6-oxo-1H-pyridin-3-yl)-2-fluorophenyl]-N-[5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-3-yl]acetamide
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| Synonyms |
GSK-3179106; GSK 3179106; GSK3179106
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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: ~93 mg/mL (~199.0 mM)
Ethanol: ~6 mg/mL (~12.8 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.35 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 (5.35 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 (5.35 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 | 2.1394 mL | 10.6972 mL | 21.3945 mL | |
| 5 mM | 0.4279 mL | 2.1394 mL | 4.2789 mL | |
| 10 mM | 0.2139 mL | 1.0697 mL | 2.1394 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 |
| NCT02798991 | Completed | Drug: GSK3179106 Drug: Matched Placebo |
Irritable Bowel Syndrome | GlaxoSmithKline | June 2016 | Phase 1 |
| NCT02727283 | Completed | Drug: GSK3179106 Drug: Placebo |
Irritable Bowel Syndrome | GlaxoSmithKline | November 26, 2015 | Phase 1 |
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