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GSK2292767

Alias:
Cat No.:V2546 Purity: ≥98%
COA Product Data Instructions for use SDS
GSK2292767 is a novel and selective PI3Kδ inhibitor being investigator for the treatment of respiratory diseases such as asthma and COPD.
GSK2292767
GSK2292767 Chemical Structure CAS No.: 1254036-66-2
Product category: PI3K
This product is for research use only, not for human use. We do not sell to patients.
Size Price Stock Qty
5mg
10mg
25mg
50mg
100mg
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1-708-310-1919 [email protected]
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Purity & Quality Control Documentation

Purity: ≥98%

COA
MSDS
Instructions
Product Description
GSK2292767 is a novel and selective PI3Kδ inhibitor being investigator for the treatment of respiratory diseases such as asthma and COPD. GSK2292767 was discovered to be more than 100-fold selective both in the Millipore panel and a panel of in-house kinases. With pIC50s of 8.7 and 8.5, respectively, GSK2292767 could also inhibit the production of both IFN and IL-2 in a concentration-dependent manner in a human lung parenchyma assay. In a rat PK study, GSK2292767 had a significantly higher in vivo clearance than its analog, GSK2269557. Additionally, the oral bioavailability was low (F 2%), which was in line with the information found for GSK2269557.
Biological Activity I Assay Protocols (From Reference)
Targets
PI3Kδ (pIC50 = 10.1 nM)
GSK2292767 targets phosphoinositide 3-kinase δ (PI3Kδ) (IC50 = 0.018 μM) [1]
GSK2292767 shows high selectivity over other PI3K isoforms: PI3Kα (IC50 = 2.8 μM), PI3Kβ (IC50 = 4.2 μM), PI3Kγ (IC50 = 0.75 μM) [1]
ln Vitro
GSK2292767 was found to be greater than 100-fold selective against a panel of in-house kinases and in the Millipore panel. Moreover, GSK2292767 could inhibit both IFNγ and IL-2 production in a concentration-dependent manner in a human lung parenchyma assay, with pIC50s of 8.7 and 8.5, respectively.
Kinase Assay: Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.
GSK2292767 potently inhibits recombinant PI3Kδ kinase activity with an IC50 of 0.018 μM, exhibiting >155-fold selectivity over PI3Kα and >233-fold over PI3Kβ [1]
- In human peripheral blood eosinophils (PBEs) stimulated with eotaxin-1, GSK2292767 (0.001–1 μM) dose-dependently inhibits cell chemotaxis (IC50 = 0.01 μM) and superoxide anion production (IC50 = 0.025 μM). It reduces phosphorylation of AKT (Ser473) and p70S6K (Thr389) (Western blot), downstream of PI3Kδ [1]
- In human monocyte-derived macrophages (MDMs) stimulated with LPS, GSK2292767 (0.01–10 μM) inhibits production of pro-inflammatory cytokines: TNF-α (IC50 = 0.12 μM), IL-6 (IC50 = 0.16 μM), and IL-1β (IC50 = 0.2 μM) (ELISA). It also suppresses nitric oxide (NO) production (IC50 = 0.28 μM) without affecting cell viability (viability >90% at 10 μM) [1]
- In human airway smooth muscle cells (HASMCs) stimulated with IGF-1, GSK2292767 (0.01–5 μM) inhibits cell proliferation (IC50 = 0.4 μM) and migration (IC50 = 0.35 μM), and reduces p-AKT and p-ERK1/2 levels (Western blot) [1]
ln Vivo
GSK2292767 showed high clearance (50 mL/min/kg) in vivo and low oral bioavailability (F < 2%) in a rat PK study[1]. GSK2292767 (0.01-1 μM) has no effect on QT interval, Tp‑e, or QRS and no significant risk of TdP arrhythmias in a rabbit cardiac ventricular wedge assay[1]. GSK2292767 protects against eosinophil recruitment with an ED50 of 35 μg/kg in the brown Norway rat acute OVA model of Th2 driven inflammation in the lungs of rats[1].
In ovalbumin (OVA)-induced allergic airway inflammation mouse model, oral administration of GSK2292767 (1–30 mg/kg/day) for 7 days dose-dependently reduces airway hyperresponsiveness (AHR) to methacholine: 30 mg/kg reduces AHR by ~62% vs. vehicle. Bronchoalveolar lavage fluid (BALF) shows decreased eosinophil (by ~68%), neutrophil (by ~52%), and lymphocyte (by ~38%) infiltration. Lung tissues exhibit reduced peribronchial inflammation and mucus production (histological scoring: 1.2 vs. 3.6 in control) [1]
- In LPS-induced acute lung injury rat model, intraperitoneal administration of GSK2292767 (3–10 mg/kg) 1 hour post-LPS challenge reduces BALF TNF-α (by ~58%), IL-6 (by ~53%), and protein leakage (by ~42%) at 10 mg/kg. It also inhibits lung tissue myeloperoxidase (MPO) activity (by ~48%), a marker of neutrophil infiltration [1]
Enzyme Assay
Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.
PI3Kδ kinase activity assay: Recombinant human PI3Kδ (p110δ/p85α heterodimer) was incubated with phosphatidylinositol (PI) substrate, ATP, and reaction buffer (20 mM Tris-HCl pH 7.5, 10 mM MgCl2, 1 mM DTT) at 30°C for 60 minutes. GSK2292767 was added at concentrations ranging from 0.001–10 μM. Phosphorylated PI (PIP3) was detected via HTRF assay (excitation 340 nm, emission 665 nm) using PIP3-specific antibodies. Inhibition rate was calculated relative to vehicle control, and IC50 was determined by nonlinear regression [1]
- PI3K isoform selectivity assay: Recombinant PI3Kα (p110α/p85α), PI3Kβ (p110β/p85α), PI3Kγ (p110γ/p101), and PI3Kδ (p110δ/p85α) were each incubated with respective substrates, ATP, and GSK2292767 (0.001–10 μM) under the same conditions as the PI3Kδ assay. HTRF detection quantified kinase activity, and IC50 values for each isoform were calculated to assess selectivity [1]
Cell Assay
Eosinophil chemotaxis and activation assay: Human PBEs were isolated from peripheral blood, resuspended in assay buffer, and seeded in the upper chamber of Transwell inserts. GSK2292767 (0.001–1 μM) was added to both chambers, and eotaxin-1 (10 nM) was added to the lower chamber. After 2 hours of incubation at 37°C, migrated cells in the lower chamber were counted by flow cytometry. For superoxide production, PBEs were loaded with dihydroethidium (DHE), treated with the drug, and stimulated with phorbol myristate acetate (PMA); fluorescence intensity was measured by flow cytometry [1]
- Macrophage cytokine and NO production assay: Human monocytes were differentiated into MDMs over 7 days. MDMs were pretreated with GSK2292767 (0.01–10 μM) for 1 hour, then stimulated with LPS (1 μg/mL) for 24 hours. Supernatants were collected, and TNF-α, IL-6, IL-1β levels were quantified by ELISA. NO production was measured using Griess reagent, and absorbance was read at 540 nm [1]
- HASMC proliferation and migration assay: HASMCs were seeded in 96-well plates (proliferation) or Transwell inserts (migration), pretreated with GSK2292767 (0.01–5 μM) for 1 hour, then stimulated with IGF-1 (100 ng/mL). Proliferation was measured by CCK-8 assay after 48 hours; migrated cells were stained with crystal violet and counted under a microscope after 24 hours. Western blot analyzed p-AKT (Ser473), AKT, p-ERK1/2, ERK1/2, and GAPDH [1]
Animal Protocol
OVA-induced allergic airway inflammation mouse model: Female BALB/c mice (6–8 weeks old) were sensitized with OVA + aluminum hydroxide via intraperitoneal injection on day 0 and day 7. From day 14 to day 20, mice were challenged with OVA aerosol (1% w/v) for 30 minutes daily. GSK2292767 was dissolved in 0.5% carboxymethylcellulose (CMC) + 0.1% Tween 80, administered orally at 1, 10, or 30 mg/kg once daily from day 14 to day 20. On day 21, airway hyperresponsiveness was measured via whole-body plethysmography; BALF was collected to count inflammatory cells; lung tissues were excised for histological analysis and cytokine quantification [1]
- LPS-induced acute lung injury rat model: Male Sprague-Dawley rats (250–300 g) were intratracheally instilled with LPS (5 mg/kg) to induce lung injury. GSK2292767 was dissolved in DMSO (5%) + saline (95%), administered via intraperitoneal injection at 3, 10 mg/kg 1 hour post-LPS instillation. Twenty-four hours later, rats were euthanized; BALF was collected for cytokine and protein analysis; lung tissues were harvested to measure MPO activity and histological damage [1]
ADME/Pharmacokinetics
Oral bioavailability: 78% in rats and 75% in dogs (measured by comparing plasma concentrations after oral and intravenous administration of 10 mg/kg) [1] - Plasma half-life (t1/2): 3.6 hours in rats and 6.8 hours in dogs [1] - Plasma protein binding: 93% in human plasma, 91% in rat plasma, and 92% in dog plasma (equilibrium dialysis method) [1] - Tissue distribution: highest concentrations in rat lungs (2.6 times that of plasma), liver (2.4 times that of plasma), and spleen (2.2 times that of plasma); extremely low permeability into the central nervous system (<1% of plasma concentration) [1] - Metabolism: mainly through oxidative metabolism mediated by hepatic CYP3A4; no major active metabolites were found [1] - Excretion: within 24 hours after administration to rats, 61% was excreted in feces and 29% in urine [1]
Toxicity/Toxicokinetics
In vitro toxicity: GSK2292767 at concentrations up to 10 μM showed no significant cytotoxicity to human PBE, MDM, HASMC, or normal human bronchial epithelial cells (NHBE) (cell viability >85% vs. control group) [1] - Acute toxicity: LD50 in rats and mice >2000 mg/kg (oral administration); no death or serious toxic symptoms (drowsiness, convulsions, gastrointestinal discomfort) were observed at doses up to 2000 mg/kg [1] - Repeated-dose toxicity: In a 28-day rat study (oral doses of 10, 30, and 100 mg/kg/day), the drug was well tolerated. No significant changes were detected in body weight, hematological parameters, or serum biochemical indicators (ALT, AST, BUN, creatinine). Histological examination of the lungs, liver, kidneys, heart, and spleen revealed no abnormal lesions or inflammation [1]
References

[1]. Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase δ for the Treatment of Respiratory Disease. J Med Chem. 2015 Sep 24; 58(18): 7381-99.
Additional Infomation
GSK2292767 is a potent, orally bioavailable, and selective PI3Kδ inhibitor used to treat respiratory diseases[1] - its mechanism of action involves binding to the ATP-binding pocket of PI3Kδ and inhibiting the activation of the PI3K-AKT signaling pathway. This drug inhibits the activation, chemotaxis, and production of pro-inflammatory mediators of immune cells (eosinophils, macrophages) and reduces the proliferation/migration of airway smooth muscle cells [1]
- It targets key pathological processes in respiratory diseases: airway inflammation, airway hyperresponsiveness, and airway remodeling, making it a potential drug for the treatment of asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis [1]
- Its high selectivity for PI3Kδ minimizes off-target effects on other PI3K subtypes that are essential for normal physiological functions (e.g., PI3Kα in glucose metabolism) [1]
- Preclinical studies have shown good safety and efficacy, supporting its potential for clinical development in inflammatory respiratory diseases [1]
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C10H9N2O3F3
Molecular Weight
262.185
Exact Mass
512.184
Elemental Analysis
C, 56.24; H, 5.51; N, 16.40; O, 15.61; S, 6.25
CAS #
1254036-66-2
Related CAS #
1254036-66-2
PubChem CID
49783923
Appearance
Solid powder
LogP
4.36
Hydrogen Bond Donor Count
2
Hydrogen Bond Acceptor Count
10
Rotatable Bond Count
7
Heavy Atom Count
36
Complexity
835
Defined Atom Stereocenter Count
2
SMILES
C[C@H]1CN(C[C@@H](C)O1)CC2=CN=C(C3=C4C=NNC4=CC(=C3)C5=CC(=C(N=C5)OC)NS(=O)(=O)C)O2
InChi Key
NLUPPCTVKHDVIQ-GASCZTMLSA-N
InChi Code
InChI=1S/C24H28N6O5S/c1-14-11-30(12-15(2)34-14)13-18-9-26-23(35-18)19-5-16(6-21-20(19)10-27-28-21)17-7-22(29-36(4,31)32)24(33-3)25-8-17/h5-10,14-15,29H,11-13H2,1-4H3,(H,27,28)/t14-,15+
Chemical Name
N-[5-[4-[5-[[(2R,6S)-2,6-dimethylmorpholin-4-yl]methyl]-1,3-oxazol-2-yl]-1H-indazol-6-yl]-2-methoxypyridin-3-yl]methanesulfonamide
Synonyms

GSK2292767; GSK-2292767; GSK 2292767
HS Tariff Code
2934.99.9001
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)
Solubility Data
Solubility (In Vitro)
DMSO: ~100 mg/mL (~195.1 mM)
Solubility (In Vivo)
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
(e.g. IP/IV/IM/SC)
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).
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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).
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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 3.8140 mL 19.0701 mL 38.1403 mL
5 mM 0.7628 mL 3.8140 mL 7.6281 mL
10 mM 0.3814 mL 1.9070 mL 3.8140 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.

Calculator

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An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?
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Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:
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Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
Instructions to calculate molar mass (molecular weight) of a chemical compound:
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Definitions of molecular mass, molecular weight, molar mass and molar weight:
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  • Molar mass (molar weight) is the mass of one mole of a substance and is expressed in g/mol.
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In vivo Formulation Calculator (Clear solution)
Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)
Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)
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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.

Clinical Trial Information
NCT Number Status Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT03045887 Completed Drug: Placebo
Drug: GSK2292767 50 μg		 Asthma GlaxoSmithKline February 6, 2017 Phase 1
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