AS-605240

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 mouse 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 mouse model of leukocyte chemotaxis with an ED₅₀ value of 9.1 mg/kg.

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3. Hennessy, B.T., Smith, D.L., Ram, P.T., et al. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat. Rev. Drug Discov. 4(12), 988-1004 (2005).

4. Rückle, T., Schwarz, M.K., and Rommel, C. PI3Kγ inhibition: Towards an 'aspirin of the 21^st century'? Nat. Rev. Drug Discov. 5(11), 903-918 (2006).

5. Camps, M., Rückle, T., Ji, H., et al. Blockade of PI3K g suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat. Med. 11(9), 936-943 (2005).