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PI3Kγ inhibition: towards an 'aspirin of the 21st century'?

Key Points

  • Phosphatidylinositol 3-kinases (PI3Ks) are lipid and protein kinases that are involved in numerous signalling pathways in various cellular contexts. The class IA PI3Ks (PI3Kα, -β and -δ) have been most extensively studied so far, but attention is now turning to the only member of class IB, PI3Kγ, a central signalling molecule that is activated by GPCRs and Ras and regulates 3′ phosphorylated phosphoinositide- and mitogen-activated protein kinase (MAPK) signalling.

  • Although PI3Kγ is involved in many pathways, its expression is confined mostly to the haematopoietic system and its activation is dependent on the co-expression of a specific GPCR, therefore, even complete inhibition of PI3Kγ is expected to only have a dampening effect on downstream signals and provides a more subtle way of intervening with a particular signal. This, and its interaction with chemokine GPCRs means that PI3Kγ has become an attractive target for inflammatory diseases.

  • Small molecules, antibodies and knock-out and knock-in mouse models have been used to validate PI3Kγ as a genuine target for chemokine-associated inflammatory disorders. In addition, this research identified non-chemokine-related signalling activity in lymph tissue but, more surprisingly, a role for PI3Kγ in regulating vasorelaxation and vasocontriction in the cardiovascular system, which indicates that PI3Kγ inhibitors could have cardio-protective potential.

  • The biggest challenge in developing small-molecule drugs against PI3Kγ is to obtain inhibitors that have good selectivity for PI3Kγ against other PI3K isoforms. Drug-design efforts have been aided by having in hand the crystal structure of PI3Kγ and two isoform-unspecific first-generation inhibitors, wortmannin and LY2394002. Co-crystal structures of PI3Kγ with these compounds are offering unique insights into the key residues for binding to PI3Kγ that should enable the development of isoform-selective inhibitors. The loop between amino-acid residues Lys883 and Thr886 near the ATP-binding pocket of PI3Kγ is particularly attractive for the rational design of a selective inhibitor because it shows the lowest degree of similarity between all PI3K isoforms.

  • In the past 3 years, there has been a significant increase in patenting activity disclosing novel PI3Kγ-inhibitor chemotypes, and reports on next-generation compounds have started to appear in the literature. No inhibitor has yet progressed to the clinic, and it will be essential to balance isoform selectivity and potency to obtain maximum efficacy. Whether success will stem from using a dual or multi-targeted approach — thereby inhibiting two or more PI3K enzymes to achieve maximal efficacy for a specific indication — or whether the best drug will potently inhibit only a single isoform, remains an area for further research.

Abstract

Class IB phosphatidylinositol 3-kinase p110γ (PI3Kγ) has gained increasing attention as a promising drug target for the treatment of inflammatory disease. Extensive target-validation data are available, which are derived from studies using both pharmacological and genetic tools. More recent findings have uncovered further therapeutic applications for PI3Kγ inhibitors, opening up potentially huge opportunities for these drugs. Several companies have been pursuing small-molecule PI3Kγ inhibitor projects, but none of them has progressed to the clinic yet. Here, we discuss the insights gained so far and the main challenges that are emerging on the path to developing PI3Kγ inhibitors for the treatment of human disease.

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Figure 1: Strategies for interfering with chemokine/chemokine-receptor-mediated processes.
Figure 2: Archetype PI3K inhibitors.
Figure 3: PI3K γ inhibition and human disease: piecing together the puzzle.
Figure 4: Synthetic PI3Kα, β and δ inhibitor chemotypes in the patent literature.
Figure 5: Chronological appearance of synthetic PI3Kγ inhibitor chemotypes in the patent literature.
Figure 6: Homology models of PI3Ks.

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Acknowledgements

We wish to thank our collaborators E. Hirsch, M. Wymann, R. Williams, A. Carrera, L. Stephens, P. Hawkins, R. Wetzker, B. Vanhaesebroeck and, in particular, J. Shaw, X. Jiang, H. Ji, V. Ardissone, R. Cirillo and M. Camps for all their insightful and inspiring discussions as well as their support during the preparation of this review. We are also grateful to C. Hebert for all graphic works and to all our friends and colleagues for their outstanding support and valuable contributions to our research.

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Correspondence to Matthias K. Schwarz or Christian Rommel.

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T.R., M.K.S. and C.R. are employees of Serono International SA, which is involved in the discovery and commercialization of therapeutics for the prevention and treatment of human diseases.

Glossary

Cell reconstitution

Bone-marrow-derived cell transfer between donor and recipient mice.

Kinase-dead knock-in

A targeted genomic point mutation in the ATP-binding site that renders the kinase enzymatically inactive.

Clamp motif

A two-point pharmacophore connected by a core structure, such as a hinge.

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Rückle, T., Schwarz, M. & Rommel, C. PI3Kγ inhibition: towards an 'aspirin of the 21st century'?. Nat Rev Drug Discov 5, 903–918 (2006). https://doi.org/10.1038/nrd2145

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