product name IC-87114
Description: IC-87114 is a selective PI3Kδ inhibitor with IC50 of 0.5 μM in a cell-free assay, 58-fold more selective for PI3Kδ than PI3Kγ, and over 100-fold more selective than PI3Kα/β. It has been reported that IC87114 reduced FMLP-induced PIP3 synthesis and chemotaxis in neutrophils. IC87114 also blocked TNF1α-stimulated elastase exocytosis from neutrophils in a mouse model of inflammation. A role for PI3Kδ in TNFα-induced signaling was demonstrated by a reduction in Akt-phosphorylation and PDK1 enzyme activity upon treatment of this cell type with IC87114. In human memory T cells, IC87114 largely inhibited T-cell receptor-induced PI(3)K signaling by both naive and effector.
References: Nat Chem Biol. 2010 Feb;6(2):82-3; Blood. 2004 May 1;103(9):3448-56.
397.43
Formula
C22H19N7O
CAS No.
371242-69-2
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 0.66 mg/mL (1.66 mM)
Water: <1 mg/mL (slightly soluble or insoluble)
Ethanol: <1 mg/mL (slightly soluble or insoluble)
Solubility (In vivo)
4% DMSO+30% PEG 300+ddH2O: 0.7 mg/mL
Chemical Name
2-[(6-aminopurin-9-yl)methyl]-5-methyl-3-(2-methylphenyl)quinazolin-4-one
other peoduct :
| In Vitro |
Kinase Assay: Phosphatidylinositol-(4,5)-bisphosphate (PIP2) containing phospholipid liposomes are prepared. Briefly, bovine PIP2 and phosphatidylserine (1:2 molar ratio) are vacuum-dried and resuspended at 1 mM PIP2 in 20 mM HEPES-KOH, pH 7.4, 50 mM NaCl, and 5 mM EDTA. The lipid suspension is subjected to a brief sonication, followed by 5 freeze-thaw cycles and then 20 extrusion cycles to produce the liposomes. The assay is conducted in 60 μL reaction volumes in 20 mM HEPES, pH 7.4, buffer containing 1 nM PI3K, 1 µM PIP2, 200 µM ATP, 1 µCi [γ-32P]ATP, 5 mM MgCl2, plus 50 µg/mL horse IgG as carrier protein. The reaction is incubated for 10 min at room temperature, quenched in 140 of 1 M K2PO4, 30 mM EDTA, pH 8.0, captured onto a 96-well polyvinylidene difluoride filter plate, and washed five times with 1 M K2PO4. The filter is allowed to dry completely, and the bound radioactivity is quantitated. IC87114 dilutions are assayed in a final concentration of 1% (w/w) DMSO. Cell Assay: For AML cell proliferation assay, BMMCs are isolated and cultured in α-medium with 5% fetal calf serum (FCS) with or without FLT-3 ligand (10 ng/mL) for 48 hours and with or without IC87114. [3H]-thymidine (1 μCi [37 kBq]) is added for a final 6 hours and the amount of radioactivity incorporated is determined by trichloracetic acid precipitation. CD34+ cells from cord blood are cultured in stem cell factor (SCF; 20 ng/mL), FLT-3 ligand (10 ng/mL), and Tpo (20 nM) for 48 hours with or without 10 μM IC87114 and pulsed for 12 hours with [3H]-thymidine. IC-87114 selectively inhibits PI3Kδ and not sensitive to PI3Kα, β, and γ. In human neutrophils, IC87114 (5 µM) potently inhibits N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated phosphatidylinositol triphosphate (PIP3) biosynthesis and chemotaxis. IC87114 (5 µM) also inhibits polarized morphology and spreading of neutrophils. In human acute myeloid leukemia (AML) blast cells, such as bone marrow mononuclear cells (BMMCs), IC87114 (10 µM) inhibits both constitutive and Flt-3-stimulated Akt phosphorylation and cell proliferation. It is also found that IC87114 (5 µM–30 µM) inhibits SCF- or IL-3-stimulated BMMC responses, which are not observed in PI3Kδ mutant (p110δD910A) cells. In anti-CD3-stimulated mice CD62L+ (naive) and CD62L− (effector/memory) CD4+ T cells, IC87114 inhibits proliferation and interferon-gamma (IFN-γ) production. The IC50 values of IC87114 are: (1) 1.2 µM and 40 nM, for CD62L+ and CD62L− cell proliferation, respectively; (2) 120 nM and 1 nM, for IFN-γ production of CD62L+ and CD62L− cells, respectively. Similar effects by IC87114 are also observed in human T cells. A recent study reveals that in chromaffin cells, IC87114 enhances the transient increase of PtdIns(4,5)P2, which results in a potentiation of exocytosis |
|---|---|
| In Vivo | In mice, IC87114 (15 mg/kg–60 mg/kg) inhibits the allergic response in the back skin and ear. In mice induced with anti-CD3 or ConA, IC87114 (30 mg/kg) reduces hypersensitivity responses and decreases plasma levels of cytokines, such as IL-2, IL-4, IL-17, IFN-γ, and tumor necrosis factor-α (TNF-α). |
| Animal model | Wild-type or PI3Kδ mutant (p110δD910A) mice (C57BL/6 or BALB/c) |
| Formulation & Dosage | Solubilized in 75% PEG200; 15-60 mg/kg; oral gavage |
| References | [1] Sadhu C, et al. J Immunol, 2003, 170(5), 2647-2654.; [2] Sujobert P, et al. Blood, 2005, 106(3), 1063-1066.; [3] Ali K, et al. Nature, 2004, 431(7011), 1007-1011. |
