2-[(6-Amino-9H-purin-9-yl)methyl]-5-methyl-3-(2-methylphenyl)-4(3H)-quinazolinone

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.

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. 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).

Description

The phosphatidylinositol 3-kinase (PI3K) signaling pathway has central roles in cell growth, development, and survival. IC-87114 is a cell-permeable selective inhibitor of the PI3K catalytic subunit p110δ (IC₅₀ = 0.5 μM). It less effectively inhibits p110γ and p110β (IC₅₀ = 29 and 75 μM, respectively) and has no significant effect on p110α and several other kinases. This product is used to elucidate the role of p110δ in cells, including neutrophils, natural killer cells, and other types of leukocytes. It has also been used in mice.

Uses

IC 87114 is a selective PI3Kδ inhibitor.

Definition

ChEBI: A member of the class of quinazolines that is quinazolin-4(3H)-one carrying (6-amino-9H-purin-9-yl)methyl, 2-methylphenyl and methyl substituents at positions 2, 3 and 5 respectively.

target

PI3Kδ

References

[1]. workman p, van montfort rl. pi(3) kinases: revealing the delta lady. nat chem biol. 2010 feb;6(2):82-3.
[2]. puri kd, doggett ta, douangpanya j, hou y, tino wt, wilson t, graf t, clayton e, turner m, hayflick js, diacovo tg. mechanisms and implications of phosphoinositide 3-kinase delta in promoting neutrophil trafficking into inflamed tissue. blood. 2004 may 1;103(9):3448-56.
[3]. soond dr, bjørgo e, moltu k, dale vq, patton dt, torgersen km, galleway f, twomey b, clark j, gaston js, taskén k, bunyard p, okkenhaug k. pi3k p110delta regulates t-cell cytokine production during primary and secondary immune responses in mice and humans. blood. 2010 mar 18;115(11):2203-13.