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Inflammation

Cooling the inflammatory response

Nature Reviews Drug Discovery volume 4, page 811 (2005)Cite this article

PI3Ks are intracellular signalling enzymes that are involved in several fundamental biological processes, such as cell survival and proliferation, and vesicular trafficking. One of the drawbacks of disrupting the activity of the PI3Ks is that some isoforms are essential for these cellular processes; for example, knockouts of the genes encoding the ubiquitously expressed PI3Kα and PI3Kβ are embryonically lethal in mice. However, targeting the PI3Kγ and PI3Kδ isoforms would circumvent this problem because their expression is restricted to the haematopoietic system. Mice lacking the genes encoding these enzymes develop normally, although they do show defects in adaptive immunity, including activation of T and B cells. This suggests that PI3Kγ and PI3Kδ could be potential targets for diseases caused by inappropriate inflammatory responses, such as rheumatoid arthritis and systemic lupus erythematosus (SLE). Indeed, PI3Kγ is known to have a key role in mediating the activation and migration of white blood cells (leukocyte chemotaxis), such as macrophages and neutrophils during an immune response, and neutrophil migration has been strongly implicated in the pathogenesis of rheumatoid arthritis.

Using an automated in vitro lipid-kinase assay, Camps et al. identified, and subsequently optimized, a series of small-molecule inhibitors of PI3Kγ. Crystallization of one of the compounds, AS-604850, with PI3Kγ facilitated the structure-based design of AS-605240, which was found to have a greater inhibitory potency towards PI3Kγ. After demonstrating the inhibitory effects of these compounds on several types of immune cells and chemokine ligands ex vivo, the authors tested the efficacy of AS-605240 in two distinct mouse models of rheumatoid arthritis. Oral administration of AS-605240 suppressed joint inflammation and damage in both models. Importantly, treatment with AS-605240 afforded the same protective effects that were observed in mice deficient in the gene encoding PI3Kγ.

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References

ORIGINAL RESEARCH PAPERS

  1. Camps, M. et al. Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nature Med. 28 August 2005 (10.1038/nm1284)

  2. Barber, D. F. et al. PI3Kγ inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus. Nature Med. 28 August 2005 (10.1038/nm1291)

FURTHER READING

  1. Smolen, J. S. & Steiner, G. Therapeutic strategies for rheumatoid arthritis. Nature Rev. Drug Discov. 2, 473–488 (2003)

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Authors
  1. Samantha Barton
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Barton, S. Cooling the inflammatory response. Nat Rev Drug Discov 4, 811 (2005). https://doi.org/10.1038/nrd1863

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