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Phosphatidylinositol 3-kinase (PI3K) catalyzes the phosphorylation of phosphatidylinositol at the three position to produce the second messengers PtdIns-(3,4)-P2 and PtdIns-(3,4,5)-P3.1,2,3 PI3Kγ is a class 1B PI3K that is composed of a p110 catalytic subunit and a p101 or p84 regulatory subunit, whereas PI3Kα, β, and δ are class 1A enzymes composed of p110 and p85 subunits4 AS-605240 is an orally active inhibitor of PI3-kinase γ that suppresses joint inflammation in murine models of rheumatoid arthritis.5 It inhibits human recombinant PI3Kγ, α, β, and δ in an ATP-competitive manner with IC50 values of 8, 60, 270, and 300 nM, respectively.5 AS-605240 inhibits C5a-mediated phosphorylation of protein kinase B in RAW 264 cells with an IC50 value of 90 nM. In vivo, AS-605240 reduced RANTES-induced peritoneal neutrophil recruitment in a murine model of leukocyte chemotaxis with an ED50 value of 9.1 mg/kg.
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1
Rameh, L.E., Cantley, L.C. The role of phosphoinositide 3-kinase lipid products in cell function. J Biol Chem 274 8347-8350 (1999).
2
Vivanco, I., Sawyers, C.L. The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nature Reviews Cancer 2 489-501 (2002).
3
Hennessy, B.T., Smith, D.L., Ram, P.T., et al. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nature Reviews Drug Discovery 4 988-1004 (2005).
4
Rückle, T., Schwarz, M.K., Rommel, C. PI3Kγ inhibition: Towards an 'aspirin of the 21st century'?. Nature Reviews Drug Discovery 5 903-918 (2006).
5
Camps, M., Rückle, T., Ji, H., et al. Blockade of PI3Kg suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nature Med 11(9) 936-943 (2005).
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