Phosphoinositide 3-kinase (PI3K)γ and PI3Kδ are expressed in rheumatoid arthritis (RA) synovium and regulate innate and adaptive immune responses. We determined the effect of a potent PI3K-δ,γ inhibitor, IPI-145, in two preclinical models of RA. IPI-145 was administered orally in rat adjuvant-induced arthritis (AA) and intraperitoneally in mouse collagen-induced arthritis (CIA). IPI-145 significantly reduced arthritis severity in both RA models using dosing regimens initiated before onset of clinical disease. Treatment of established arthritis with IPI-145 decreased arthritis progression in AA but not CIA. In AA, histology scores, radiographic joint damage, and matrix MMP-13 expression were reduced in IPI-145-treated rats. In CIA, joint histology scores and expression of MMP-3 and MMP-13 mRNA were lower in the IPI-145 early treatment group. These data show that IPI-145 is a potential therapy for RA.
See article at J Pharmacol Exp Ther 2014, 348:271–280.
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