Antibodies
GDC-0834
- 貨號 Cat. No.
- S7022
- 規格 Size
- 5~200mg
- 品牌 Brand
- Selleckchem
Description
GDC-0834
Catalog No.S7022
GDC-0834 is a novel potent and selective BTK inhibitor with IC50 of 5.9 nM.
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Biological Activity
| Description | GDC-0834 is a novel potent and selective BTK inhibitor with IC50 of 5.9 nM. | |||||
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| Targets | BTK | |||||
| IC50 | 5.9 nM [1] | |||||
| In vitro | GDC-0834 is a highly selective, reversible, ATP competitive small molecule inhibitor of BTK being developed as a therapeutic agent for Rheumatoid arthritis (RA). GDC-0834 inhibits BTK with an in vitro IC50 of 5.9 nM and 6.4 nM in biochemical and cellular assays, respectively, and in vivo IC50 of 1.1 and 5.6 μM in mouse and rat, respectively. In B cells, GDC-0834 effectively blocks B-cell antigen receptor-and CD40-mediated activation and proliferation. In monocytes, it potently inhibits immune complex-mediated inflammatory cytokine production, including tumor necrosis factor-α, which may also contribute to disease pathogenesis in RA. [1] | |||||
| In vivo | GDC-0834 inhibits BTK with an in vivo IC50 of 1.1 and 5.6 μM in mouse and rat, respectively. Administration of GDC-0834 (30–100 mg/kg) in a rat collagen-induced arthritis (CIA) model results in a dose-dependent decrease of ankle swelling and reduction of morphologic pathology. Administration of GDC-0834 results in a dose-dependent reduction of severity of the arthritic condition characteristic of CIA rats. At a dose of 100 mg/kg b.i.d. GDC-0834, synovitis and periarticular inflammation are mild, whereas cartilage damage, pannus, and bone destruction are minimal in the ankles of arthritic rats. [1] In vitro metabolite identification studies in hepatocytes reveals predominant formation of an inactive metabolite (M1) via amide hydrolysis in human. The formation of M1 appeares to be NADPH-independent in human liver microsomes. M1 is found in only minor to moderate quantities in plasma from preclinical species dosed with GDC-0834. GDC-0834 exhibits low clearance in PXB chimeric mice with humanized liver. [2] | |||||
| Features | ||||||
Protocol(Only for Reference)
Kinase Assay: [1]
| Measurement of BTK Enzyme Inhibition by GDC-0834 | Btk activity is quantified by determining phosphorylation of an exogenous peptide product in a Lanthascreen assay. In the validation of the assay conditions, both enzyme concentration and time dependence experiments are performed ensuring linearity at 60 min before assessing compound potency. The Km values for ATP and peptide are also assessed before selecting the final reaction conditions. In a final reaction volume of 25 μL, Btk [human, full-length, C-terminal V5–6 × His, expressed in Sf9 cells; 0.075 ng/25 μL reaction) is incubated with 50 mM HEPES, pH 7.5, 10 mM MgCl2, 2 mM MnCl2, 2 mM dithiothreitol, 0.2 mM NaVO4, 0.01% casein, 0.01% Triton X-100, 2.5% glycerol, and 0.4 μM fluorescein poly-Glu/Ala/Tyr]. The reaction is initiated by the addition of ATP to 25 μM (Km of ATP). After incubation for 60 min at room temperature, the reaction is stopped by the addition of a final concentration of 2 nM Tb-PY20 detection antibody in 60 mM EDTA for 30 min at room temperature. Detection is determined on a PerkinElmer Envision with 340-nM excitation and emission at 495 and 520 nm. The response versus BTK inhibitor concentration data are fitted with GraphPad Prism version 5.00. |
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Animal Study: [1]
| Animal Models | BALB/c mice |
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| Dosages | 25, 50, 100, and 150 mg/kg |
| Administration | oral |
References
Chemical Information
| Molecular Weight (MW) | 596.74 |
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| Formula | C33H36N6O3S |
| CAS No. | 1133432-50-4 |
| Storage | 3 years -20℃Powder |
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| 6 months-80℃in DMSO | |
| Syonnyms | N/A |
| Solubility (25°C) * | In vitro | DMSO | mg/mL (<1 mM) |
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| Water | mg/mL (<1 mM) | ||
| Ethanol | mg/mL (<1 mM) | ||
| * <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. | |||
| Chemical Name | Benzo[b]thiophene-2-carboxamide, N-[3-[6-[[4-[(2S)-1,4-dimethyl-3-oxo-2-piperazinyl]phenyl]amino]-4,5-dihydro-4-methyl-5-oxo-2-pyrazinyl]-2-methylphenyl]-4,5,6,7-tetrahydro- |
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