Blockade of PI3K suppresses joint inflammation and damage in mouse models of rheumatoid arthritis

Montserrat Camps^1, 5, Thomas Rückle^1, 5, Hong Ji^1, 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

¹  Serono Pharmaceutical Research Institute, Serono International S.A., 14, Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland.

²  LCG-RBM, Serono International S.A., Via Ribes 1, 10010 Colleretto Giacosa, Italy.

³  Department of Genetics, Biology and Biochemistry, University of Torino, Via Santena 5bis, 10126 Torino, Italy.

⁴  Department of Clinical & Biological Sciences, Institute of Biochemistry & Genetics, Centre of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.

⁵  These authors contributed equally to this work.

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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