The discovery of a selective PI3Kγ inhibitor reveals a role for PI3Kγ in TH17 cell function.

  • Major finding: The discovery of a selective PI3Kγ inhibitor reveals a role for PI3Kγ in TH17 cell function.

  • Mechanism: CZC24832 suppresses RORγt expression and reduces the number of IL-17A–producing cells.

  • Impact: Selective PI3Kγ inhibition may impair the activity of tumor-associated TH17 cells.

The class I phosphoinositide 3-kinases (PI3K) are attractive targets for antitumor therapy, but selective targeting of PI3K isoforms has been hampered by the close structural similarities among the PI3Ks and other lipid kinases. Bergamini and colleagues developed a strategy to identify compounds that selectively inhibit PI3Kγ, a PI3K isoform that has previously been linked to inflammation. Briefly, compound libraries were screened in cell extracts for their ability to compete with a matrix of nonspecific PI3K and lipid kinase inhibitors, and matrix-bound proteins were eluted and spotted onto a nitrocellulose membrane to allow high-throughput detection of compounds that reduced PI3Kγ binding to the inhibitor matrix. A highly selective and potent ATP-competitive PI3Kγ inhibitor, CZC24832, was identified with suitable pharmacokinetic properties and oral bioavailability that suppressed inflammatory responses in mouse models in a dose-dependent manner. The authors treated primary human immune cells exposed to inflammatory signals with CZC24832 and found that T-cell interleukin 17A (IL-17A) production was strongly inhibited. Because IL-17A production is a hallmark of the distinct subset of CD4+ helper T cells known as TH17 cells, the authors tested the effect of CZC24832 on TH17 cell differentiation. CZC24832 reduced expression of retinoic acid receptor–related orphan receptor γt (RORγt), a transcription factor that drives TH17 differentiation, and decreased the number of IL-17A–producing cells. Importantly, both PI3Kγ and TH17 cells have been implicated in the recruitment of inflammatory cells to tumors that can promote angiogenesis, immunosuppression, and tumor growth. Selective inhibition of PI3Kγ may therefore be a useful strategy to target tumor inflammation.

Bergamini G, Bell K, Shimamura S, Werner T, Cansfield A, Müller K, et al. A selective inhibitor reveals PI3Kγ dependence of TH17 cell differentiation. Nat Chem Biol 2012 Apr 29 [Epub ahead of print].

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