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Article
Nature Medicine 11, 936 - 943 (2005)
Published online: 28 August 2005 | doi:10.1038/nm1284
Blockade of PI3K
suppresses joint inflammation and damage in mouse models of rheumatoid arthritis
Montserrat Camps1,5, Thomas Rückle1,5, Hong Ji1,5, Vittoria Ardissone2, Felix Rintelen1, Jeffrey Shaw1, Chiara Ferrandi2, Christian Chabert1, Corine Gillieron1, Bernard Françon1, Thierry Martin1, Denise Gretener1, Dominique Perrin1, Didier Leroy1, Pierre-Alain Vitte1, Emilio Hirsch3, Matthias P Wymann4, Rocco Cirillo2, Matthias K Schwarz1 & Christian Rommel1
Abstract
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 PI3K
(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 PI3K as a therapeutic target. We also describe that oral treatment with a PI3K 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 PI3K inhibitors as potential therapeutic molecules for the treatment of chronic inflammatory disorders such as rheumatoid arthritis.
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