2. Metabolic Enzyme/Protease
  3. Serpin Ser/Thr Protease
  4. GSK716

GSK716 (A1AT modulator 1) is an orally active Z α1-antitrypsin (Z-A1AT) inhibitor with a pIC50 of 8.3. GSK716 binds a cryptic Z α1-antitrypsin pocket, stabilizes monomeric folding intermediates, blocks polymerization, and increases monomer secretion. GSK716 acts on select sensitive α1-antitrypsin variants but fails to affect resistant variants. GSK716 can be used for the research of α1-antitrypsin deficiency and α1-antitrypsin deficiency-associated liver disease.

For research use only. We do not sell to patients.

GSK716

GSK716 Chemical Structure

CAS No. : 2406205-61-4

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Solid + Solvent (Highly Recommended)
10 mM * 1 mL in DMSO
ready for reconstitution
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GSK716 Related Antibodies

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  • Biological Activity

  • Purity & Documentation

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Description

GSK716 (A1AT modulator 1) is an orally active Z α1-antitrypsin (Z-A1AT) inhibitor with a pIC50 of 8.3. GSK716 binds a cryptic Z α1-antitrypsin pocket, stabilizes monomeric folding intermediates, blocks polymerization, and increases monomer secretion. GSK716 acts on select sensitive α1-antitrypsin variants but fails to affect resistant variants. GSK716 can be used for the research of α1-antitrypsin deficiency and α1-antitrypsin deficiency-associated liver disease[1][2][3].

In Vitro

GSK716 (72 h) potently inhibits in vitro polymerisation of plasma-purified Z α1-antitrypsin with a mean pIC50 of 8.3[1].
GSK716 binds selectively to monomeric Z α1-antitrypsin with a mean pKd of 8.5, showing 50-fold lower affinity for wild-type M α1-antitrypsin and no binding to polymeric Z α1-antitrypsin[1].
GSK716 (50 µM) stabilises both Z and wild-type M α1-antitrypsin against heat-induced unfolding, as shown by increased transition midpoint temperatures in a SYPRO Orange thermal stability assay[1].
GSK716 (1:50 to 1:1 molar ratios of GSK716 to protein) corrects misfolding of Z α1-antitrypsin during rapid refolding from urea denaturation, restoring monomeric conformation at stoichiometric and higher concentrations[1].
GSK716 (50 µM) abolishes the protease inhibitory activity of Z and wild-type M α1-antitrypsin but does not interfere with the inhibitory activity of other related serpins[1].
GSK716 completely blocks intracellular polymerisation of Z α1-antitrypsin in CHO-TET-ON-Z-A1AT cells (mean pIC50 6.3) and increases its secretion (mean pEC50 6.2), while restoring ER stress sensitivity to wild-type levels[1].
GSK716 inhibits intracellular polymerisation of Z α1-antitrypsin in ZZ iPSC-derived human hepatocytes (mean pIC50 6.4), increases its secretion by approximately threefold (mean pEC50 6.5), and promotes clearance of pre-existing intracellular polymers[1].
GSK716 (10-100 μM; 48 h) potently inhibits intracellular polymerization and promotes secretion of sensitive AAT variants (including Z AAT) in Hepa 1.6 cells[2].
GSK716 (40 nM (fluorescent derivative for Z-A1AT); 2 μM (fluorescent derivative for M-A1AT); overnight at room temperature, 3 days at 4°C plus 6 hours at room temperature) binds to purified Z-alpha-1-antitrypsin with a high affinity Kd of 1.5 nM, demonstrating 200-fold faster association kinetics with Z-alpha-1-antitrypsin compared to M-alpha-1-antitrypsin[3].
GSK716 (50 μM; heated from 25°C to 95°C at 1°C/min) increases the native state stability of purified M-alpha-1-antitrypsin and Z-alpha-1-antitrypsin against heat-induced unfolding[3].
GSK716 (10 μM; 2-hour pre-incubation, followed by 4-hour heat incubation at 48-65°C) blocks heat-induced polymerisation of purified plasma-derived Z-alpha-1-antitrypsin in vitro[3].
GSK716 (0-50 μM; 4-hour denaturation, 1-hour refolding incubation) promotes the refolding of denatured purified M-alpha-1-antitrypsin and Z-alpha-1-antitrypsin into native, non-polymerised monomers[3].
GSK716 inhibits intracellular Z-alpha-1-antitrypsin polymer formation (pIC50 = 6.4) and increases Z-alpha-1-antitrypsin secretion by approximately 3-fold (pEC50 = 6.5) in iPSC-derived ZZ-alpha-1-antitrypsin hepatocytes[3].
GSK716 (10 μM) restores tunicamycin sensitivity of Z-alpha-1-antitrypsin-expressing CHO-TET-ON-Z-A1AT cells to the level of wild-type M-alpha-1-antitrypsin-expressing cells by abrogating intracellular polymer formation[3].
GSK716 binds to a cryptic site on recombinant Cys232Ser alpha-1-antitrypsin, inducing conformational changes that stabilise the protein and prevent polymerisation[3].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

GSK716 Related Antibodies
In Vivo

GSK716 (10-100 mg/kg; p.o.; three times a day; 6-20 days) produces a dose-dependent increase in circulating monomeric Z α1-antitrypsin in transgenic mice, with a mean sevenfold increase at the 100 mg/kg three-times-daily dose, while showing no significant reduction in hepatic polymer load over 20 days[1].
GSK716 (10-100 mg/kg; p.o.; three times a day; 3-20 days) dose-dependently increases circulating monomeric Z α1-antitrypsin levels by up to 8-fold in transgenic mice with alpha-1-antitrypsin deficiency, but does not reduce established liver polymer burden within 20 days of dosing[3].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: Hemizygous female Z α1-antitrypsin transgenic mice (13-15 weeks of age)[1]
Dosage: 10 mg/kg; 30 mg/kg; 100 mg/kg
Administration: p.o.; three times a day; 6 days (10, 30 mg/kg); 6, 15, 20 days (100 mg/kg)
Result: Resulted in a significant dose-dependent increase in circulating monomeric Z α1-antitrypsin relative to pre-dose levels (10 mg/kg).
Resulted in a larger significant dose-dependent increase in circulating monomeric Z α1-antitrypsin relative to pre-dose levels (30 mg/kg).
Resulted in a mean sevenfold increase in circulating monomeric Z α1-antitrypsin levels after 6 days, a mean sevenfold to eightfold increase after 15 and 21 days, and a fourfold increase in intrahepatic Z α1-antitrypsin monomer levels (100 mg/kg).
Molecular Weight

370.42

Formula

C21H23FN2O3
CAS No.
Appearance

Solid

Color

White to off-white

SMILES

O=C(C1=CC=CC2=C1CC(N2)=O)N[C@@H]([C@H](C3=CC=CC(F)=C3C)O)CCC
Shipping

Room temperature in continental US; may vary elsewhere.
Storage
Powder -20°C 3 years
4°C 2 years
In solvent -80°C 6 months
-20°C 1 month
Solvent & Solubility
In Vitro: 

DMSO : 100 mg/mL (269.96 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

Preparing
Stock Solutions
Concentration Solvent Mass 1 mg 5 mg 10 mg
1 mM 2.6996 mL 13.4982 mL 26.9964 mL
5 mM 0.5399 mL 2.6996 mL 5.3993 mL
View the Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

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  • Dilution Calculator

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Concentration (start) × Volume (start) = Concentration (final) × Volume (final)

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In Vivo:

Select the appropriate dissolution method based on your experimental animal and administration route.

For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for in vivo experiments, it is recommended to prepare freshly and use it on the same day.
The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.

  • Protocol 1

    Add each solvent one by one:  10% DMSO    40% PEG300    5% Tween-80    45% Saline

    Solubility: 2.5 mg/mL (6.75 mM); Clear solution; Need ultrasonic

    This protocol yields a clear solution of 2.5 mg/mL.

    Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.

    Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
  • Protocol 2

    Add each solvent one by one:  10% DMSO    90% (20% SBE-β-CD in Saline)

    Solubility: 2.5 mg/mL (6.75 mM); Clear solution; Need ultrasonic

    This protocol yields a clear solution of 2.5 mg/mL.

    Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.

    Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
In Vivo Dissolution Calculator
Please enter the basic information of animal experiments:

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Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
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Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Calculation results:
Working solution concentration: mg/mL
Method for preparing stock solution: mg drug dissolved in μL  DMSO (Stock solution concentration: mg/mL).
The concentration of the stock solution you require exceeds the measured solubility. The following solution is for reference only. If necessary, please contact MedChemExpress (MCE).
Method for preparing in vivo working solution for animal experiments: Take μL DMSO stock solution, add μL . μL , mix evenly, next add μL Tween 80, mix evenly, then add μL Saline.
 If the continuous dosing period exceeds half a month, please choose this protocol carefully.
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
Purity & Documentation
References

Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

Optional Solvent Concentration Solvent Mass 1 mg 5 mg 10 mg 25 mg
DMSO 1 mM 2.6996 mL 13.4982 mL 26.9964 mL 67.4910 mL
5 mM 0.5399 mL 2.6996 mL 5.3993 mL 13.4982 mL
10 mM 0.2700 mL 1.3498 mL 2.6996 mL 6.7491 mL
15 mM 0.1800 mL 0.8999 mL 1.7998 mL 4.4994 mL
20 mM 0.1350 mL 0.6749 mL 1.3498 mL 3.3745 mL
25 mM 0.1080 mL 0.5399 mL 1.0799 mL 2.6996 mL
30 mM 0.0900 mL 0.4499 mL 0.8999 mL 2.2497 mL
40 mM 0.0675 mL 0.3375 mL 0.6749 mL 1.6873 mL
50 mM 0.0540 mL 0.2700 mL 0.5399 mL 1.3498 mL
60 mM 0.0450 mL 0.2250 mL 0.4499 mL 1.1248 mL
80 mM 0.0337 mL 0.1687 mL 0.3375 mL 0.8436 mL
100 mM 0.0270 mL 0.1350 mL 0.2700 mL 0.6749 mL
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GSK716 Related Classifications

Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

GSK7162406205-61-4A1AT modulator 1GSK 716GSK-716SerpinSer/Thr ProteaseSerine protease inhibitors (Serpins)Serine proteasesSerine endopeptidasesThreonine proteasesCHO-TET-ON-Z-A1AT cellsrecombinant Cys232Ser alpha-1-antitrypsinZZ iPSC-derived human hepatocytesα1-antitrypsin deficiencytransgenic miceZ α1-antitrypsinserpinsHepa 1.6 cellsα1-antitrypsin deficiency-associated liver diseasewild-type M α1-antitrypsinInhibitorinhibitorinhibit

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