IC-87114

• Catalog No.: S1268
• CAS Number: 371242-69-2
• M. F.: C22H19N7O
• M. W.: 397.43256
• Storage: -20°C

SYNONYMS

• IUPAC name: 2-[(6-amino-9H-purin-9-yl)methyl]-5-methyl-3-(2-methylphenyl)-3,4-dihydroquinazolin-4-one
• IUPAC Traditional name: 2-[(6-aminopurin-9-yl)methyl]-5-methyl-3-(2-methylphenyl)quinazolin-4-one
• Synonyms: PIK 293

DATABASE IDS

• CAS Number: 371242-69-2

PROPERTIES

• Target: PI3K
• Salt Data: Free Base
• Solubility: DMSO
• Storage Condition: -20°C

DETAILS

Description (English)

Research Area

• Description: Cancer

Biological Activity

• Description: IC-87114 is a selective inhibitor of PI3Kδ with IC50 of 0.5 μM.
• Targets: PI3Kδ; PI3Kβ; PI3Kγ
• IC50: 0.5 μM; 75 μM; 29 μM ^[1]
• In Vitro: 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. ^[1]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. ^[2] 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 (p110δ^D910A) cells. ^[3]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. ^[4]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. ^[5]
• In Vivo: In mice, IC87114 (15 mg/kg–60 mg/kg) inhibits the allergic response in the back skin and ear. ^[3]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). ^[4]

Protocol

• Protocol: Kinase Assay ^[1]
• PI3K 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 μL 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.
• Protocol: Cell Assay ^[2]
• Cell Lines: Human bone marrow mononuclear cells (BMMCs) and CD34^+ cells
• Concentrations: 0–100 μM
• Incubation Time: 48 hours
• Methods: 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.
• Protocol: Animal Study ^[3]
• Animal Models: Wild-type or PI3Kδ mutant (p110δ^D910A) mice (C57BL/6 or BALB/c)
• Formulation: Dissolved in 75% PEG200
• Doses: 15 mg/kg–60 mg/kg
• Administration: Oral gavage

References

• References: [1] Sadhu C, et al. J Immunol, 2003, 170(5), 2647-2654.
• References: [2] Sujobert P, et al. Blood, 2005, 106(3), 1063-1066.
• References: [3] Ali K, et al. Nature, 2004, 431(7011), 1007-1011.
• References: [4] Soond DR, et al. Blood, 2010, 115(11), 2203-2213.
• References: [5] Wen PJ, et al. Nat Commun, 2011, doi:10.1038/ncomms1500.

REFERENCES

• Sadhu C, et al. J Immunol, 2003, 170(5), 2647-2654.
• Sujobert P, et al. Blood, 2005, 106(3), 1063-1066.
• Ali K, et al. Nature, 2004, 431(7011), 1007-1011.
• Soond DR, et al. Blood, 2010, 115(11), 2203-2213.
• Wen PJ, et al. Nat Commun, 2011, doi:10.1038/ncomms1500.