Uses
Potent and selective phosphoinositide 3-kinase (PI(3)K) p110γ inhibitor shown to be selective for class IB PI(3)K-mediated cellular effects.
Biological Activity
as-252424 is a potent, selective and novel small-molecule pi3kγ inhibitor (ic50= 30 nm)pi3k (phosphatidylinositol-4,5-bisphosphate 3-kinase) is a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. it plays a key role in pi3k/akt/mtor pathway.in thp-1 (human monocytic cell line), as-252424 inhibited the phosphorylation of pkb/akt due to mcp1 binding to the gpcr receptor ccr2 at lowest ic50 values of 0.4 μm. in primary monocytes and monocytic wild-type cell line thp-1, as-252424 inhibited mcp-1-mediated chemotaxis in a concentration-dependent manner (ic50 value= 52 μm and 53 μm, respectively). [1] in capan 1 and hpaf (pancreatic cancer cell lines), as52424 specifically inhibited the cell proliferation. [2]in a mouse model of thioglycollate-induced peritonitis, oral administration of as-252424 at 10 mg/kg led to moderate reduction of neutrophil recruitment (35% ±14%). [1]
Biochem/physiol Actions
AS-252424 is a potent and selective phosphoinositide 3-kinase PI3Kγ inhibitor with IC50 = 30 nM in a mouse model.
Enzyme inhibitor
This novel and potent protein kinase inhibitor (FW = 305.28 g/mol; CAS
900515-16-4; Solubility: 60 mg/mL DMSO), also known as (Z) -5- ( (5- (4-
fluoro-2-hydroxyphenyl) furan-2-yl) methylene) thiazolidine-2,4-dione,
targets PI3Kγ (IC50 = 30 nM) in a cell-free assay, showing 30x greater
selectivity toward PI3Kγ versus PI3Kα and much lower inhibitory activity
toward PI3Kβ and PI3Kδ.
Enzyme inhibitor
This potent and selective PI3K inhibitor (FW = 305.28 g/mol; CAS
900515-16-4), also known as (5Z) -5-[[5- (4-fluoro-2-hydroxyphenyl) -2-
furanyl]methylene]-2,4-thiazolidinedione, targets human recombinant
PI3Ka (IC50 = 30 nM), with far weaker inhibition of PI3Kb (IC50 = 940
nM), PI3Kg (IC50 = 20,000 nM), and PI3Kd (IC50 = 20,000 nM). These
intracellular signal-transducing enzymes phosphorylate the position-3
hydroxyl in phosphatidylinositol (PtdIns). Oral administration of
AS252424 in a mouse model for acute peritonitis led to a significant
reduction of leukocyte recruitment.
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].
IC 50
PI3Kγ: 30 nM (IC50); PI3Kα: 935 nM (IC50); PI3Kδ: 20 μM (IC50); PI3Kβ: 20 μM (IC50)
References
1. pomel v, klicic j, covini d 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):3857-71.2. edling ce, selvaggi f, buus r et al. key role of phosphoinositide 3-kinase class ib in pancreatic cancer. clin cancer res. 2010 oct 15;16(20):4928-37.
