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Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis


Phosphoinositide 3-kinases (PI3K) have long been considered promising drug targets for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. But the lack of specificity, isoform selectivity and poor biopharmaceutical profile of PI3K inhibitors have so far hampered rigorous disease-relevant target validation. Here we describe the identification and development of specific, selective and orally active small-molecule inhibitors of PI3Kγ (encoded by Pik3cg). We show that Pik3cg−/− mice are largely protected in mouse models of rheumatoid arthritis; this protection correlates with defective neutrophil migration, further validating PI3Kγ as a therapeutic target. We also describe that oral treatment with a PI3Kγ inhibitor suppresses the progression of joint inflammation and damage in two distinct mouse models of rheumatoid arthritis, reproducing the protective effects shown by Pik3cg−/− mice. Our results identify selective PI3Kγ inhibitors as potential therapeutic molecules for the treatment of chronic inflammatory disorders such as rheumatoid arthritis.

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Figure 1: Inhibitory profile and binding mode of PI3K inhibitors.
Figure 2: PI3Kγ inhibitors block chemoattractant-mediated PKB phosphorylation in macrophages and primary monocytes.
Figure 3: Effects of PI3Kγ inhibitors on in vitro and in vivo chemotaxis.
Figure 4: Elimination of PI3Kγ function largely protects against αCII-IA.
Figure 5: Effects of AS-605240 in mouse CIA.

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We thank E. Ammanati, M. Carbonatto and S. Carboni for technical support and P. Gaillard, D. Church, T. Vallotton-Grippi, M. Maio and D. Covini for support in chemistry, A. Proudfoot's team for protein chemistry and C. Retzler and J. Hassa for advice. We are thankful to R. Williams for advice and technical support for crystallization. We further thank B. Vanhaesebroeck, K. Okkenhaug, R. Wetzker and in particular A. Carrera for support, advice and enthusiasm throughout the project, L. Stephens for advice and K. Jeffrey for critical reading of the manuscript. We are grateful to C. Hebert for graphic support, C. Mark for editorial support and P. Cavioli for administrative assistance. We especially thank M. Kosco-Vilbois for encouragement when this project was initiated. We thank S. Arkinstall and T. Wells for support throughout the entire study. This work was supported by European Union Fifth Framework Program QLG1-2001-02171 to E.H., M.P.W. and C.R.

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Correspondence to Christian Rommel.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Determination of the kinetic parameters of the four different PI3K isoforms. (PDF 43 kb)

Supplementary Fig. 2

Kinase selectivity profile of LY294002, AS-604850, AS-605240 and AS-605091. (PDF 21 kb)

Supplementary Fig. 3

Determination of in vitro and in vivo pharmacological parameters of AS-605240. (PDF 20 kb)

Supplementary Table 1

Enzymatic parameters for Class I PI3Kγ isoforms, obtained from the experiments shown in Supplementary Fig. 1. (PDF 13 kb)

Supplementary Table 2

Summary of the crystallographic information obtained from PI3Kγ crystals soaked with AS-604850 and AS-605240. (PDF 19 kb)

Supplementary Table 3

Selectivity profile of PI3K inhibitors for Class I PI3K isoforms. (PDF 12 kb)

Supplementary Methods (PDF 31 kb)

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Camps, M., Rückle, T., Ji, H. et al. Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat Med 11, 936–943 (2005).

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