Novel phosphoinositide 3-kinase delta,gamma inhibitor: potent anti-inflammatory effects and joint protection in models of rheumatoid arthritis.

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Boyle DL, Kim HR, Topolewski K, Bartok B, Firestein GS

Novel phosphoinositide 3-kinase delta,gamma inhibitor: potent anti-inflammatory effects and joint protection in models of rheumatoid arthritis.

J Pharmacol Exp Ther. 2014 Feb;348(2):271-80. doi: 10.1124/jpet.113.205955. Epub 2013 Nov 15.

PubMed ID

24244039 [ View in PubMed

]

Abstract

Phosphoinositide 3-kinases gamma and delta (PI3Kgamma and PI3Kdelta) are expressed in rheumatoid arthritis (RA) synovium and regulate innate and adaptive immune responses. We determined the effect of a potent PI3Kdelta,gamma 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). Efficacy was assessed by paw swelling, clinical scores, histopathology and radiography, and microcomputed tomography scanning. Gene expression and Akt phosphorylation in joint tissues were determined by quantitative real-time polymerase chain reaction and Western blot analysis. Serum concentrations of anti-type II collagen (CII) IgG and IgE were measured by immunoassay. T-cell responses to CII were assayed using thymidine incorporation and immunoassay. 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 in AA, but not CIA, significantly decreased arthritis progression. In AA, histology scores, radiographic joint damage, and matrix metalloproteinase (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 than in the vehicle group. The ratio of anti-CII IgG2a to total IgG in CIA was modestly reduced. Interleukin-17 production in response to CII was decreased in the IPI-145-treated group, suggesting an inhibitory effect on T-helper cell 17 differentiation. These data show that PI3Kdelta,gamma inhibition suppresses inflammatory arthritis, as well as bone and cartilage damage, through effects on innate and adaptive immunity and that IPI-145 is a potential therapy for RA.

DrugBank Data that Cites this Article

Drugs

Duvelisib

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Duvelisib	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform	Protein	Humans	Yes	Inhibitor	Details
Duvelisib	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform	Protein	Humans	Yes	Inhibitor	Details