AS-252424

Names

[ Name ]:
AS-252424

[Synonym ]:
2,4-Thiazolidinedione, 5-[[5-(4-fluoro-2-hydroxyphenyl)-2-furanyl]methylene]-, (5Z)-
(5Z)-5-{[5-(4-Fluoro-2-hydroxyphenyl)-2-furyl]methylene}-1,3-thiazolidine-2,4-dione
(5Z)-5-{[5-(4-fluoro-2-hydroxyphenyl)furan-2-yl]methylidene}-1,3-thiazolidine-2,4-dione
AS-252424

Biological Activity

[Description]:

AS-252424 is a potent and selective PI3Kγ inhibitor with an IC50 of 30±10 nM.

[Related Catalog]:

Research Areas >> Cancer

[Target]

PI3Kγ:30 nM (IC50)

PI3Kα:935 nM (IC50)

PI3Kδ:20 μM (IC50)

PI3Kβ:20 μM (IC50)

[In Vitro]

AS-252424 also inhibits PI3Kα, PI3Kβ and PI3Kδ with IC50s of 935±150 nM, 20 μM and 20 μM, respectively. AS-252424 inhibits MCP-1-mediated chemotaxis in wild-type primary monocytes in a concentration-dependent manner with an IC50 value of 52 μM, as well as in the monocytic cell line THP-1 with an IC50 value of 53 μM. In the human monocytic cell line THP-1, MCP-1 binding to the GPCR chemokine receptor CCR2, strongly induces phosphorylation of PKB/Akt, which is effectively inhibited by AS-252424 at IC50 values as low as 0.4 μM. In contrast, induction of PKB/Akt phosphorylation by colony stimulating factor (CSF-1), binding to the growth factor receptor c-fms, is only blocked by AS-252424 at IC50 values as high as 4.7 μM[1].

[In Vivo]

Oral administration of AS-252424 in a mouse model of acute peritonitis leads to a significant reduction of leukocyte recruitment. To evaluate the efficacy of AS-252424 to block leukocyte migration in vivo, it is tested in a mouse model of thioglycollate-induced peritonitis. Oral administration of AS-252424 at 10 mg/kg results in moderate reduction of neutrophil recruitment (35%±14%), almost matching the result observed in PI3Kγ-deficient mice. Given the short oral half-life of AS-252424 (t1/2=1 h) and relative high clearance (2.25 L/kg per h), investigations at later time points (24-48 h) to assess macrophage and monoycyte recruitment are not undertaken. The modest pharmacokinetic properties do not appear to be caused by rapid oxidative metabolism (microsomal metabolism after 1 h: 16% (rat), 10% (human))[1].

[Kinase Assay]

A PI3Kγ lipid kinase assay, based on the neomycin-coated scintillation proximity assay (SPA) bead technology, is performed in 384-well plates using ATP/[γ33P]ATP and PtdIns. Kinase assays for IC50 value determinations with PI3Kα, PI3Kβ, and PI3Kδ are carried out[1].

[Cell Assay]

After 3 h of starvation in serum-free medium, Raw-264 macrophages are pretreated with inhibitors (e.g., AS-252424, 1 nM, 10 nM, 100 nM, 1 μM, 10 μM and 100 μM) or DMSO for 30 min and stimulated for 5 min with 50 nM C5a. PKB/Akt phosphorylation is monitored using phospho-Ser-473 Akt specific antibody and standard ELISA protocols[1].

[Animal admin]

Mice[1] PI3Kγ knockout (KO) mice are used. Oral administration of AS-252424 at 10 mg/kg is performed in PI3Kγ-deficient mice.

[References]

[1]. Pomel V, et al. Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase gamma. J Med Chem. 2006 Jun 29;49(13):3857-71.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.6±0.1 g/cm3

[ Molecular Formula ]:
C₁₄H₈FNO₄S

[ Molecular Weight ]:
305.281

[ Exact Mass ]:
305.015808

[ PSA ]:
104.84000

[ LogP ]:
2.14

[ Appearance of Characters ]:
yellow

[ Index of Refraction ]:
1.692

[ Storage condition ]:
2-8°C

[ Water Solubility ]:
DMSO: >20mg/mL

Safety Information

[ Personal Protective Equipment ]:
Eyeshields;Gloves;type N95 (US);type P1 (EN143) respirator filter

[ RIDADR ]:
NONH for all modes of transport

Articles

Profound blockade of T cell activation requires concomitant inhibition of different class I PI3K isoforms.

Immunol. Res. 62 , 175-88, (2015)

PI3K inhibitors have emerged as potential therapeutic tools for a variety of diseases, and thus, a vast array of compounds with specificity for different PI3K isoforms is being developed. Gaining know...

Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase gamma.

J. Med. Chem. 49 , 3857-3871, (2006)

Class I phosphoinositide 3-kinases (PI3Ks), in particular PI3Kgamma, have become attractive drug targets for inflammatory and autoimmune diseases. Here, we disclose a novel series of furan-2-ylmethyle...

Inhibition of PI3K prevents the proliferation and differentiation of human lung fibroblasts into myofibroblasts: the role of class I P110 isoforms.

PLoS ONE 6 , e24663, (2011)

Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disease characterized by an accumulation of fibroblasts and myofibroblasts in the alveolar wall. Even though the pathogenesis of...