GSK3335103
GSK3335103 is an orally active non-peptidic αvβ6 integrin inhibitor with a pIC50 of 8 and a pKi of 9.96. GSK3335103 blocks αvβ6 integrin-mediated cell adhesion and TGF-β1 activation, induces integrin internalization, recycling and lysosomal degradation, attenuates TGFβ signaling and reduces collagen deposition. GSK3335103 decreases the level of pSmad2 in BAL cells and collagen deposition in lung tissues in a mouse model of pulmonary fibrosis. GSK3335103 can be used in research related to pulmonary fibrosis.
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- CAS No.: 1893340-21-0
- Formule: C27H36FN3O4
- Masse moléculaire:485.59
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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Chemical Information
- Protocole
- Pureté et documentation
- Références
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Help & FAQs
Activité biologique
Description
IC50 & Target
[1]|
αvβ6 8 (pIC50) |
αvβ6 9.96 (pKi) |
In Vitro
GSK3335103 (43d) potently inhibits αvβ6 integrin (pIC50 = 8.0), exhibits only weak activity against other αv integrins, and shows low inhibitory effect on hERG channels[1].
The artificial membrane permeability of GSK3335103 is 146 nm/s[2].
GSK3335103 has a low intrinsic clearance, which is 20-35 mL/min/kg in rat hepatocytes and less than 21 mL/min/kg in human hepatocytes[2].
After incubation with GSK3335103 (3 μM; 60 min) at 37°C, its permeability in MDCK cells (AP/BL + efflux inhibitor) reaches 87 nm/s[2].
The kinetic solubility of GSK3335103 is ≥238 μg/mL[2].
GSK3335103 (6 h) binds with high affinity to αvβ6 integrin from recombinant human, mouse, and idiopathic pulmonary fibrosis (IPF) lung tissues[3].
GSK3335103 (2-48 h) potently inhibits αvβ6-mediated TGFβ signaling pathway by reducing pSmad2 levels[3].
GSK3335103 (0.1-16 nM) induces rapid, concentration-dependent endocytosis of αvβ6 in NHBE cells, and αvβ6 rapidly recycles back to the cell surface after drug washout; prolonged exposure, however, leads to lysosome-dependent degradation of αvβ6[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
Parmacokinetics
| Species | Dose | Route | CLblood | CLunbound | T1/2 | Vss | Bioavailability | MRT | Cmax | AUC |
|---|---|---|---|---|---|---|---|---|---|---|
| Rat[1] | 1 mg/kg | i.v. | 20 mL/min/kg | 54 mL/min/kg | 4.3 h | 3.6 L/kg | / | / | / | / |
| Rat[1] | 2 mg/kg | p.o. | / | / | / | / | 93 % | / | / | / |
| Dog[1] | 1 mg/kg | i.v. | 3.7 mL/min/kg | 12 mL/min/kg | 4.8 h | 1.4 L/kg | / | / | / | / |
| Dog[1] | 1 mg/kg | p.o. | / | / | / | / | 104 % | / | / | / |
| Pig[1] | 1 mg/kg | i.v. | 5.6 mL/min/kg | 21 mL/min/kg | 2.7 h | 0.9 L/kg | / | / | / | / |
| Pig[1] | 1 mg/kg | p.o. | / | / | / | / | 84 % | / | / | / |
| Rat[2] | 1 mg/kg | i.v. | 20 mL/min/kg | 54 mL/min/kg | / | 3.6 L/kg | / | 3.0 h | / | / |
| Rat[2] | 1 mg/kg | p.o. | / | / | / | / | 93 % | / | 530 ng/mL | 776 ng·h/mL |
In Vivo
GSK3335103 (0.08-2 mg/kg; p.o.; single administration) inhibits the binding of αvβ6-specific ligands, and suppresses the TGFβ-mediated pSmad2 signaling pathway in lung tissues and bronchoalveolar lavage (BAL) cells of bleomycin-induced fibrotic mice[3].
GSK3335103 (15 mg/kg; p.o.; twice daily; for 7 consecutive days) reduces Bleomycin-induced TGFβ signaling and collagen deposition levels in the lungs of fibrotic mice to levels comparable to those in healthy control mice[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Mice[1]
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Dosage:2 mg/kg; 10 mg/kg; 15 mg/kg
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Administration:p.o.
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Result:Demonstrated sustained inhibition of pharmacodynamic and fibrotic end points across the tested dose range, with a clear link between effect and unbound plasma concentration.
Achieved >90% αvβ6 target engagement at trough concentrations, which equates to a human equivalent dose range of 10-75 mg b.i.d.
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Animal Model:C57BL/6 (male, 6-12 weeks old, 17-29 g, bleomycin-induced pulmonary fibrosis)[3]
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Dosage:2 mg/kg
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Administration:p.o.; single dose; 2 or 8 h prior to imaging
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Result:Reduced 111In-DTPA-A20FMDV2 binding to αvβ6 in the lungs to 78% of vehicle control at 2 h post-dosing.
Reduced 111In-DTPA-A20FMDV2 binding to αvβ6 in the lungs to 76% of vehicle control at 8 h post-dosing.
Showed no significant difference in binding reduction between the 2 h and 8 h groups.
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Animal Model:C57BL/6 (male, 6-12 weeks old, 17-29 g, bleomycin-induced pulmonary fibrosis)[3]
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Dosage:0.08 mg/kg; 0.15 mg/kg; 0.3 mg/kg; 0.4 mg/kg; 2 mg/kg
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Administration:p.o.; single dose; 4 h prior to collection (0.08, 0.15, 0.3, 0.4 mg/kg); p.o.; single dose; 2 h, 4 h, 8 h, 16 h, or 24 h prior to collection (2 mg/kg)
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Result:Reduced lung pSmad2/tSmad2 ratio by 45% at 2 h, 6% at 4 h, and increased the ratio by 8% at 8 h post-dosing with 2 mg/kg dose, with no significant inhibition at 16 h or 24 h.
Reduced BAL cell pSmad2/tSmad2 ratio by 76% at 2 h, 61% at 4 h, and 59% at 8 h post-dosing with 2 mg/kg dose.
Determined an in vivo IC50 of 3.5 ng/mL (pIC50 8.22) for inhibition of lung pSmad2 relative to unbound blood concentrations.
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Animal Model:C57BL/6 (male, 6-12 weeks old, 17-29 g, bleomycin-induced pulmonary fibrosis)[3]
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Dosage:15 mg/kg
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Administration:p.o.; twice daily; 7 days (starting day 14 post-bleomycin)
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Result:Significantly reduced pSmad2/tSmad2 ratios in BAL cells compared to vehicle-treated bleomycin-challenged mice.
Significantly reduced total lung collagen (measured as hydroxyproline) compared to vehicle-treated bleomycin-challenged mice.
Resulted in lung collagen levels not significantly different from those in saline-treated control mice.
Chemical Information
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CAS No. 1893340-21-0
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Masse moléculaire 485.59
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Formule C27H36FN3O4
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SMILES
O=C(O)C[C@@H](C1=CC=CC(OCCOC)=C1)CN2C[C@@](CCC3=NC4=C(CCCN4)C=C3)(F)CC2
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Protocole
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Fibrosis/Collagen Morphometry
Fibrosis and collagen morphometry is based on the quantitative visualization of fibrillar collagen deposition in tissue sections using histochemical stains such as Sirius Red (Picrosirius Red) or Masson's trichrome, followed by image-based or polarization-enhanced analysis to estimate collagen proportional area as a surrogate of extracellular matrix accumulation during fibrotic remodeling. Sirius Red combined with polarized light microscopy enhances detection of collagen fibers due to birefringence properties, enabling more specific visualization of collagen type I and III fibrils compared to conventional bright-field histology, while whole-section or region-restricted digital morphometry reduces field-selection bias in fibrosis assessment. Alternative quantitative approaches include second harmonic generation (SHG) and two-photon excited fluorescence microscopy, which enable label-free detection of fibrillar collagen and have been validated against histological staining and biochemica
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Collagen: Sirius Red Staining
Sirius Red or picrosirius red staining is a histochemical method for visualizing collagen-rich extracellular matrix in tissue sections, and collagen fibers are detected as red-stained structures under bright-field microscopy with enhanced birefringence under polarized light. Picrosirius red is useful for assessing total collagen organization, distribution, and fibrosis burden, but polarized color should not be interpreted as a definitive collagen type I versus type III readout because color is affected by fiber orientation, thickness, and packing.
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Connective Tissue: Masson's Trichrome/Collagen Trichrome Staining
Masson’s Trichrome (collagen/trichrome staining) is a histological technique that differentially stains tissue compartments using sequential acidic dyes to distinguish collagen from muscle and cytoplasmic components based on dye affinity and tissue permeability differences, enabling visualization of fibrosis and connective tissue architecture in histological sections. The classical formulation typically uses Weigert's iron hematoxylin for nuclear staining, Biebrich scarlet-acid fuchsin for cytoplasm and muscle, and aniline blue (or light green variants) for collagen, producing a characteristic blue/green collagen signal contrasted against red cytoplasm and dark nuclei. The staining principle relies on selective displacement of smaller dye molecules by larger anionic dyes in collagen-rich regions under controlled acidified conditions, which enhances collagen-specific dye retention. This property makes the method widely used for fibrosis assessment in organs such as heart, liver, lung, a
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Lysosome and acidic-vesicle live-cell staining
Lysosome and acidic-vesicle live-cell staining detects acidic intracellular compartments by using membrane-permeant acidotropic probes that accumulate in low-pH vesicles, including lysosomes, late endosomes, autolysosomes, and acidic phagosomes. LysoTracker staining is commonly used as an intensity-based readout of acidic lysosomal compartment abundance or enlargement, while acridine orange produces green fluorescence in less concentrated compartments and red fluorescence after concentration-dependent accumulation in acidic vesicular organelles. Loss or reduction of acridine-orange red signal can be used as a readout of lysosomal membrane permeabilization or reduced acidic-vesicle integrity. This protocol is designed for live cultured cells and can be adapted for fluorescence microscopy, high-content imaging, plate-reader readout, or flow cytometry when the selected literature supports the readout. Because these dyes report acidotropic accumulation rather than lysosome identity alone,
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How to Choose the Right Model Animal
Choosing the right model animal is a validity-driven decision in which the species, strain, sex, age, genetic background, disease-induction method, outcome measures, and welfare burden must match the scientific question rather than laboratory tradition or convenience. A model should be selected by judging face validity, construct validity, and predictive validity: whether it resembles the human phenotype, whether it reproduces relevant mechanisms, and whether results are likely to predict human biology or treatment response. Animal studies often fail to translate because of species differences, weak disease resemblance, poor experimental design, inadequate reporting, publication bias, and underuse of randomization, blinding, and sample-size justification. Unresolved questions include how to rank competing models objectively, how much human-disease complexity must be reproduced for a given objective, and when non-animal systems such as organoids, ex vivo tissue, or computational models
Pureté et documentation
Références
[1]. Procopiou PA, et al. Discovery and Development of Highly Potent and Orally Bioavailable Nonpeptidic αβ Integrin Inhibitors. Journal of medicinal chemistry. 2024 Oct 10;67(19):17497-17519. [Content Brief]
[2]. Hryczanek HF, et al. Core Modifications of GSK3335103 toward Orally Bioavailable αβ Inhibitors with Improved Synthetic Tractability. Journal of medicinal chemistry. 2024 Nov 14;67(21):19689-19715. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
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