Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

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

Nature Reviews Drug Discovery volume 5, pages 903–918 (2006)Cite this article

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.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Finan, P. M. & Ward, S. G. PI3-kinase inhibition: a target for therapeutic intervention. Protein Tyrosine Kinases 53–69 (2006).

  2. Wymann, M. P. & Marone, R. Phosphoinositide 3-kinase in disease: timing, location, and scaffolding. Curr. Opin. Cell Biol. 17, 141–149 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Fishman, M. C. & Porter, J. A. Pharmaceuticals: a new grammar for drug discovery. Nature 437, 491–493 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Cantley, L. C. The phosphoinositide 3-kinase pathway. Science 296, 1655–1657 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Rameh, L. E. & Cantley, L. C. The role of phosphoinositide 3-kinase lipid products in cell function. J. Biol. Chem. 274, 8347–8350 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Pasquali, C. & Rommel, C. Fishing for pharmaceutically relevant phosphoinositide-binding proteins using chemical proteomics. Functional Lipidomics 211–241 (2006).

  7. Weiss-Haljiti, C. et al. Involvement of phosphoinositide 3-kinase γ, Rac, and PAK signaling in chemokine-induced macrophage migration. J. Biol. Chem. 41, 43273–84 (2004).

    Article  CAS  Google Scholar 

  8. Foster, F. M., Traer, C. M., Abraham, S. M. & Fry, M. J. The phosphoinositide (PI) 3-kinase family. J. Cell Sci. 116, 3037–3040 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Vanhaesebroeck, B. et al. Synthesis and function of 3-phosphorylated inositol lipids. Annu. Rev. Biochem. 70, 535–602 (2001). A fine, comprehensive review about the role, regulation and function of class I PI3K signaling.

    Article  CAS  PubMed  Google Scholar 

  10. Engelman J. A., Luo J., Cantley L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nature Rev. Genet. 7, 606–619 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Bi, L., Okabe, I., Bernard, D. J., Wynshaw-Boris, A. & Nussbaum, R. L. Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110α subunit of phosphoinositide 3-kinase. J. Biol. Chem. 274, 10963–10968 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Bi, L., Okabe, I., Bernard, D. J. & Nussbaum, R. L. Early embryonic lethality in mice deficient in the p110β catalytic subunit of PI 3-kinase. Mammalian Genome 13, 169–172 (2002).

    CAS  PubMed  Google Scholar 

  13. Foukas, L. C., et al. Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441, 366–370 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Knight, Z. A., et al. A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling. Cell 125, 733–747 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Samuels, Y. et al. Brevia: high frequency of mutations of the PIK3Ca gene in human cancers. Science 304, 554 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Bader, A. G., Kang, S., Zhao, L. Vogt, P. K. Oncogenic PI3K deregulates transcription and translation. Nature Rev. Cancer 5, 921–929 (2005).

    Article  CAS  Google Scholar 

  17. Jackson, S. P. PI3-kinase p110β: a new target for antithrombotic therapy. Nature Med. 11, 507–514 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Okkenhaug, K., Vanhaesebroeck, B. PI3K in lymphocyte development, differentiation and activation. Nature Rev. Immunol. 3, 317–330 (2003).

    Article  CAS  Google Scholar 

  19. Stephens, L. et al. A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G-protein βγ subunits. Cell 77, 83–93 (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Stoyanov, B. et al. Cloning and characterization of a G-protein activated human phosphoinositide 3-kinase. Science 269, 690–693 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Stephens, L. R. et al. The Gβγ sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101. Cell 89, 105–114 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Krugmann, S., Hawkins, P. T., Pryer, N. & Braselmann, S. Characterizing the interactions between the two subunits of the p101/p110 phosphoinositide 3-kinase and their role in the activation of this enzyme by G subunits. J. Biol. Chem. 274, 17152–17158 (1999). References 19–22 report elegant studies delineating the regulation of PI3Kγ by Gβγ and p101 adaptor by GPCRs.

    Article  CAS  PubMed  Google Scholar 

  23. Pacold, M. E. et al. Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase γ. Cell 103, 931–943 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Suire, S., Hawkins, P. & Stephens, L. Activation of phosphoinositide 3-kinase γ by Ras. Curr. Biol. 12, 1068–1075 (2002). References 19,20 describe key studies offering structural insights into the way Ras regulates PI3Kγ activity via direct interaction.

    Article  CAS  PubMed  Google Scholar 

  25. Bondeva, T. et al. Bifurcation of lipid and protein kinase signals of PI3Kγ to the protein kinases PKB and MAPK. Science. 282, 293–296 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Lopez-Ilasaca, M., Gutkind, J. S. & Wetzker, R. Phosphoinositide 3-kinase γ is a mediator of Gβγ-dependent Jun kinase activation. J. Biol. Chem. 273, 2505–2508 (1998). References 20,21 report for the first time on the capacity of PI3Kγ to control MAPK cascades in a way that is partially independent of its lipid kinase activity.

    Article  CAS  PubMed  Google Scholar 

  27. Bernstein, H.-G., Keilhoff, G., Reiser, M., Freese, S. & Wetzker, R. Tissue distribution and subcellular localization of a G-protein coupled phosphoinositide 3-kinase. An immunohistochemical study. Cell. Mol. Biol. 44, 973–983 (1998).

    CAS  PubMed  Google Scholar 

  28. Wetzker, R. & Rommel, C. Phosphoinositide 3-kinases as targets for therapeutic intervention. Curr. Pharm. Des. 10, 1915–1922 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. McCudden, C. R., Hains, M. D., Kimple, R. J., Siderovski, D. P. & Willard, F. S. G-protein signaling: back to the future. Cell. Mol. Life Sci. 62, 551–577 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hepler, J. R. & Gilman, A. G. G proteins. Trends Biochem. Sci. 17, 383–387 (1992).

    Article  CAS  PubMed  Google Scholar 

  31. Taussig, R., Tang, W. J., Hepler, J. R. & Gilman, A. G. Distinct patterns of bidirectional regulation of mammalian adenylyl cyclases. J. Biol. Chem. 269, 6093–6100 (1994).

    CAS  PubMed  Google Scholar 

  32. Lee, S. B., Shin, S. H., Hepler, J. R., Gilman, A. G. & Rhee, S. G. Activation of phospholipase C-β2 mutants by G protein αθ and βγ subunits. J. Biol. Chem. 268, 25952–25957 (1993).

    CAS  PubMed  Google Scholar 

  33. Li, Z. et al. Roles of PLC-β2 and-β3 and PI3Kγ in chemoattractant-mediated signal transduction. Science 287, 1046–1049 (2000). Rebirth of PI3Kγ as a potential drug target for inflammation: References 33, 37 and 38 are seminal articles identifying the pivotal role of PI3Kγ in chemoattractant mediated leukocyte migration and oxidative burst.

    Article  CAS  PubMed  Google Scholar 

  34. Chodniewicz, D. & Zhelev, D. V. Chemoattractant receptor-stimulated F-actin polymerization in the human neutrophil is signaled by 2 distinct pathways. Blood 101, 1181–1184 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Chung, C. Y., Lee, S., Briscoe, C., Ellsworth, C. & Firtel, R. A. Role of Rac in controlling the actin cytoskeleton and chemotaxis in motile cells. Proc. Natl Acad. Sci. USA 97, 5225–5230 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dascal, N. Ion-channel regulation by G proteins. Trends Endocrinol. Metab. 12, 391–398 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Hirsch, E. et al. Central role for G protein-coupled phosphoinositide 3-kinase γ in inflammation. Science 287, 1049–1053 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Sasaki, T. et al. Function of PI3Kγ in thymocyte development, T cell activation, and neutrophil migration. Science 287, 1040–1046 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Patrucco, E. et al. PI3Kγ modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and-independent effects. Cell 118, 375–387 (2004). This elegant study delineates the expression and the functions of PI3Kγ in the heart, and furnishes experimental evidence of its dual role as lipid kinase and protein scaffold.

    Article  CAS  PubMed  Google Scholar 

  40. Barbier, M. et al. Tumour biology. Weakening link to colorectal cancer? Nature 413, 796 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Proudfoot, A. E. I., Power, C. A., Rommel, C. & Wells, T. N. C. Strategies for chemokine antagonists as therapeutics. Semin. Immunol. 15, 57–65 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Johnson, Z. et al. Chemokine inhibition – why, when, where, which and how? Biochem. Soc. Trans. 32, 366–377 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Onuffer, J. J. & Horuk, R. Chemokines, chemokine receptors and small-molecule antagonists: recent developments. Trends Pharm. Sci. 23, 459–467 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Ribeiro, S. & Horuk, R. The clinical potential of chemokine receptor antagonists. Pharm. Ther. 107, 44–58 (2005).

    Article  CAS  Google Scholar 

  45. Schroff, R. W. et al. The toxicology of chemokine inhibition. Mini-Rev. Med. Chem. 5, 849–855 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Arcaro, A. & Wymann, M. P. Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: the role of phosphatidylinositol 3,4,5-triphosphate in neutrophil responses. Biochem. J. 296, 297–301 (1993). Prominent article describing wortmannin as an inhibitor of class I PI3K enzymatic activity and reporting lipid signaling in neutrophils.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Vlahos, C. J., Matter, W. F., Hui, K. Y. & Brown, R. F. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J. Biol. Chem. 269, 5241–5248 (1994). Important article describing the discovery and development of the first broad-spectrum class I PI3K small-molecule kinase inhibitor, LY294002.

    CAS  PubMed  Google Scholar 

  48. Al-Aoukaty, A., Rolstad, B. & Maghazachi, A. A. Recruitment of pleckstrin and phosphoinositide 3-kinase γ into the cell membranes, and their association with Gβγ after activation of NK cells with chemokines. J. Immunol. 162, 3249–3255 (1999).

    CAS  PubMed  Google Scholar 

  49. Pillinger, M. H. & Abramson, S. B. The neutrophil in rheumatoid arthritis. Rheum. Dis. Clin. North Am. 21, 691–714 (1995).

    CAS  PubMed  Google Scholar 

  50. Thomas, M. J. et al. Airway inflammation: chemokine-induced neutrophilia and the class I phosphoinositide 3-kinases. Eur. J. Immunol. 35, 1283–1291 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Condliffe, A. M. et al. Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils. Blood 106, 1432–1440 (2005). Key article delineating the interplay of PI3Kγ and PI3Kδ in ROS production by neutrophils.

    Article  CAS  PubMed  Google Scholar 

  52. Puri, K. D. et al. The role of endothelial PI3Kγ activity in neutrophil trafficking. Blood 106, 150–157 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Jones, G. E. et al. Requirement for PI 3-kinase γ in macrophage migration to MCP-1 and CSF-1. Exp. Cell Res. 290, 120–131 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Del Prete, A. et al. Defective dendritic cell migration and activation of adaptive immunity in PI3Kγ-deficient mice. EMBO J. 23, 3505–3515 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pinho, V. et al. Phosphoinositide-3 kinases critically regulate the recruitment and survival of eosinophils in vivo: importance for the resolution of allergic inflammation. J. Leukoc. Biol. 77, 800–810 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Reif, K. et al. Differential roles for phosphoinositide 3-kinases, p110γ and p110δ, in lymphocyte chemotaxis and homing. J. Immunol. 173, 2236–2240 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Ward, S. G. Do phosphoinositide 3-kinases direct lymphocyte navigation? Trends Immunol. 25, 67–74 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Cronshaw, D. G., Owen, C., Brown, Z. & Ward, S. G. Activation of phosphoinositide 3-kinases by the CCR4 ligand macrophage-derived chemokine is a dispensable signal for T lymphocyte chemotaxis. J. Immunol. 172, 7761–7770 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Barber, D. F. et al. Class IB-phosphatidylinositol 3-kinase (PI3K) deficiency ameliorates IA-PI3K-induced systemic lupus but not T cell invasion. J. Immunol. 176, 589–593 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Nombela-Arrieta, C. et al. Differential requirements for DOCK2 and phosphoinositide-3-kinase γ during T and B lymphocyte homing. Immunity 21, 429–441 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Gilfillan, A. M. & Tkaczyk, C. Integrated signalling pathways for mast-cell activation. Nature Rev. Immunol. 6, 218–230 (2006).

    Article  CAS  Google Scholar 

  62. Laffargue, M. et al. Phosphoinositide 3-kinase γ is an essential amplifier of mast cell function. Immunity 16, 441–451 (2002). Prominent article on the regulation and function of PI3Kγ in immune-complex signaling in mast cells and allergic responses.

    Article  CAS  PubMed  Google Scholar 

  63. Hirsch, E. et al. Resistance to thromboembolism in PI3Kγ-deficient mice. FASEB J. 15, 2019–2021 (2001). An imperative read on the regulation and function of PI3Kγ in platelet aggregation.

    Article  CAS  PubMed  Google Scholar 

  64. Lian, L. et al. The relative role of PLCβ and PI3Kγ in platelet activation. Blood 106, 110–117 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Deane, J. A. & Fruman, D. A. Phosphoinositide 3-kinase: diverse roles in immune cell activation. Annu. Rev. Immunol. 22, 563–598 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Rodriguez-Borlado, L. et al. Phosphatidylinositol 3-kinase regulates the CD4/CD8 T cell differentiation ratio. J. Immunol. 170, 4475–4482 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Viard, P. et al. Gβγ dimers stimulate vascular 1-type Ca2+ channels via phosphoinositide 3-kinase. FASEB J. 13, 685–694 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Seki, T., Yokoshiki, H., Sunagawa, M., Nakamura, M. & Sperelakis, N. Angiotensin II stimulation of Ca2+-channel current in vascular smooth muscle cells is inhibited by lavendustin-A and LY-294002. Pfluegers Archiv. 437, 317–323 (1999).

    Article  CAS  PubMed  Google Scholar 

  69. Quignard, J-F. et al. Phosphoinositide 3-kinase γ mediates angiotensin II-induced stimulation of L-type calcium channels in vascular myocytes. J. Biol. Chem. 276, 32545–32551 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Steinberg, S. F. PI3King the L-type calcium channel activation mechanism. Circulation Res. 89, 641–644 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Vecchione, C. et al. Protection from angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3Kγ. J. Exp. Med. 201, 1217–1228 (2005). Important article describing the role of PI3Kγ in angiotensin signaling and vasoconstriction.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Welch, H. C., Coadwell, W. J., Stephens, L. R. & Hawkins, P. T. Phosphoinositide 3-kinase-dependent activation of Rac. FEBS Lett. 546, 93–97 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Esposito, G., Rapacciuolo, A., Naga Prasad, S. V. & Rockman, H. A. Cardiac hypertrophy: role of G protein-coupled receptors. J. Card. Fail. 8, S409–S414 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Crackower, M. A. et al. Regulation of myocardial contractility and cell size by distinct PI3K–PTEN signaling pathways. Cell 110, 737–749 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Oudit, G. Y. et al. Phosphoinositide 3-kinase γ-deficient mice are protected from isoproterenol-induced heart failure. Circulation 108, 2147–2152 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Fife, B. T., Huffnagle, G. B., Kuziel, W. A. & Karpus, W. J. CC chemokine receptor 2 is critical for induction of experimental autoimmune encephalomyelitis. J. Exp. Med. 192, 899–905 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Grant, E. P. et al. Essential role for the C5a receptor in regulating the effector phase of synovial infiltration and joint destruction in experimental arthritis. J. Exp. Med. 196, 1461–1471 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Szekanecz, Z., Kim, J. & Koch, A. E. Chemokines and chemokine receptors in reumatoid arthritis. Semin. Immunol. 15, 15–21 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. Lee, D. M. et al. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 297, 1689–1692 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Camps, M. et al. A small molecule inhibitor of PI3Kγ suppresses joint inflammation and damage in a murine model of rheumatoid arthritis. Nature Med. 11, 936–943 (2005). Key study validating PI3Kγ as a promising target for the treatment of rheumatoid arthritis, using a combination of genetic and pharmacological tools. First report of an orally active PI3Kγ small-molecule inhibitor.

    Article  CAS  PubMed  Google Scholar 

  81. Lupia, E. et al. Ablation of phosphoinositide 3-kinase-γ reduces the severity of acute pancreatitis. Am. J. Pathol. 165, 2003–2011 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Barber, D. F. et al. PI3Kg inhibition blocks glomerulonephritis and extends lifespan in murine models of systemic lupus. Nature Med. 11, 933–935 (2005). Important study validating PI3Kγ as a promising target for the treatment of SLE.

    Article  CAS  PubMed  Google Scholar 

  83. Vanhaesebroeck, B., Rohn, J. L. & Waterfield, M. D. Gene targeting: attention to detail. Cell 118, 274–276 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Clayton, E. et al. A crucial role for the p110δ subunit of phosphatidylinositol 3-kinase in B cell development and activation. J. Exp. Med. 196, 753–763 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Jou, S-T., Carpino, N., Takahashi, Y., Piekorz, R., Chao, J-R., Carpino, N., Wang, D. & Ihle, J. N. Essential, nonredundant role for the phosphoinositide 3-kinase p110δ in signaling by the B-cell receptor complex. Mol. Cell. Biol. 22, 8580–8591 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Okkenhaug, K. et al. Impaired B and T cell antigen receptor signaling in p110δ PI 3-kinase mutant mice. Science 297, 1031–1034 (2002).

    CAS  PubMed  Google Scholar 

  87. Walker, E. H., Perisic, O., Ried, C., Stephens, L. & Williams, R. L. Structural insights into phosphoinositide 3-kinase signaling. Nature 402, 313–320 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Walker, E. H. et al. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myrecetin, and staurosporin. Mol. Cell 6, 909–919 (2000). References 87 and 88 are seminal articles in the area of structure-based design of PI3Kγ inhibitors that describe the high-resolution crystal structure of PI3Kγ and binding modes of several small-molecule inhibitors.

    Article  CAS  PubMed  Google Scholar 

  89. Wipf, P. & Halter, R. J. Chemistry and biology of wortmannin. Org. Biomol. Chem. 3, 2053–2061 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Ward, S., Sotsios, Y., Dowden, J., Bruce, I. & Finan, P. Therapeutic potential of phosphoinositide 3-kinase inhibitors. Chem. Biol. 10, 207–213 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Dodge, J. A., Sato, M. & Vlahos, C. J. Inhibition of phosphatidylinositol 3-kinase with viridin, demethoxyviridin, viridiol, demethoxyviridiol, virone, wortmannolone, and analogs thereof. US Patent 05,726,167 (1995).

  92. Ihle, N. T. et al. Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol. Cancer Ther. 3, 763–772 (2004).

    CAS  PubMed  Google Scholar 

  93. Wymann, M. P. et al. Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate. Mol. Cell. Biol. 16, 1722–1733 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Sadhu C., Masinosky B., Dick K., Sowell C. G. & Staunton D. E. Essential role of phosphoinositide 3-kinase in neutrophil directional movement. J. Immunol. 170, 2647–2654 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Pomel, V. et al. Furan-2-ylmethylene thiazolidinediones as novel, potent, and selective inhibitors of phosphoinositide 3-kinase γ. J. Med. Chem. 49, 3857–3871 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Knight, Z. A. et al. Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffold. Bioorg. Med. Chem. 12, 4749–4759 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Dermatakis, A. ATP-competitive inhibitors of cyclin-dependent kinases. Front. Biotech. Pharm. 3, 125–156 (2002).

    CAS  Google Scholar 

  98. Misra, R. N. et al. N-(Cycloalkylamino)acyl-2- aminothiazole inhibitors of cyclin-dependent kinase 2. N-[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a highly efficacious and selective antitumor agent. J. Med. Chem. 47, 1719–1728 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Helal, C. J. et al. Discovery and SAR of 2-aminothiazole inhibitors of cyclin-dependent kinase 5/p25 as a potential treatment for Alzheimer's disease. Bioorg. Med. Chem. Lett. 14, 5521–5525 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Kim, K. S. et al. Discovery of aminothiazole inhibitors of cyclin-dependent kinase 2: synthesis, X-ray crystallographic analysis, and biological activities. J. Med. Chem. 45, 3905–3927 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Wityak, J. et al. Discovery and initial SAR of 2-amino-5-carboxamidothiazoles as inhibitors of the Src-family kinase p56Lck. Bioorg. Med. Chem. Lett. 13, 4007–4010 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Bruce, I. et al. 5-Phenylthiazole derivatives and their use as phosphatidylinositol 3-kinase (PI3K) inhibitors for the treatment of allergic and inflammatory diseases. PCT Int. Appl., WO-03072557 (2003).

  103. Bloomfield, G. C., Bruce, I., Leblanc, C., Oza, M. S. & Whitehead, L. Preparation of 5-phenylthiazoles as phosphatidylinositol 3-kinase (PI3 kinase) inhibitors. PCT Int. Appl., WO-04078754 (2004).

  104. Bruce, I. et al. Preparation of pyrazinyl/pyridinyl thiazolylamines as inhibitors of phosphatidylinositol 3-kinase. PCT Int. Appl., WO-04096797 (2004).

  105. Bloomfield, G. C. et al. Preparation of phenyl-thiazolylureas as inhibitors of phosphatidylinositol 3-kinase. PCT Int. Appl., WO-05021519 (2005).

  106. Quattropani, A. et al. Preparation of thiazole derivatives as modulators of the phosphoinositide 3-kinases (PI3Ks). PCT Int. Appl., WO-05068444 (2005).

  107. Breitfelder, S. et al. PI3 kinases. PCT Int. Appl., WO-06040279 (2006).

  108. Barvian, N. C., Kolz, C. N., Para, K. S., Patt, W. C. & Visnick, M. Preparation of benzoxazin-3-ones and derivatives as inhibitors of PI3K kinase for treating inflammations, cardiovascular diseases and cancers. PCT Int. Appl., WO-04052373 (2004).

  109. Gogliotti, R. D., Muccioli, K. L., Para, K. S. & Visnick, M. Preparation of benzoxazines and related compounds as inhibitors of PI3Ks. PCT Int. Appl., WO-04056820 (2004).

  110. Lanni, T. B. Jr et al. Design and synthesis of 3-methyl-5-substituted benzyl and phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3kinase γ. MBCF meeting, Clearwater Beach, Feb. 26-March 1, 2006.

  111. Rueckle, T., Jiang, X., Gaillard, P., Church, D. D. & Vallotton, T. Preparation of azolidinone-vinyl fused-benzene derivatives for therapeutic uses as PI3 kinase inhibitors. PCT Int. Appl., WO-04007491 (2004).

  112. Rueckle, T. et al. Identification and development of azolidinone vinyl-fused benzene derivatives, as potent and selective PI3Kγ inhibitors, orally active in models of rheumatoid arthritis. Abstracts of Papers, 230th National Meeting of the American Chemical Society, Washington, DC, August. 28 through September 1 2005.

  113. Para, K. S., Stankovic, C. J. & Visnick, M. Preparation of 3-substituted indoles as inhibitors of phosphoinositide-3 kinases (PI3Ks). PCT Int. Appl., WO-04108708 (2004).

  114. Gogliotti, R. D., Lee, H. T., Sexton, K. E. & Visnick, M. Preparation of tetrazolyl benzofurancarboxamides as phosphoinositide-3-kinase (PI3K) inhibitors for the treatment of cancer, inflammatory and cardiovascular diseases. PCT Int. Appl., WO-04108709 (2004).

  115. Connolly, M. et al. Preparation of N-tetrazolyl benzo[b]thiophenecarboxamides as phosphoinositide-3-kinase (PI3K) inhibitors for the treatment of cancer, inflammatory and cardiovascular diseases. PCT Int. Appl., WO-04108713 (2004).

  116. Bruendl, M. M. et al. Preparation of N-tetrazolyl benzo[b]thiophenecarboxamides as phosphoinositide-3-kinase (PI3K) inhibitors for the treatment of cancer, inflammatory and cardiovascular diseases. PCT Int. Appl., WO-04108715 (2004).

  117. Connolly, M. K., Gogliotti, R. D., Hurt, C. R., Reichard, G. A. & Visnick, M. Preparation of halo-substituted N-tetrazolylbenzo[b]thiophenecarboxamides with PI3K inhibitory activity as therapeutic agents. PCT Int. Appl., WO-05023800 (2005).

  118. Connolly, M. K., Gogliotti, R. D., Plummer, M. S. & Visnick, M. Preparation of morpholinyl-pyrimidine derivatives as inhibitors of phosphoinositide-3-kinases. PCT Int. Appl., WO-05042519 (2005).

  119. Wrasidlo, W. et al. Preparation of vasculostatic agents and methods of use. PCT Int. Appl., WO-04030635 (2004).

  120. Wrasidlo, W. Discovery of 3,3′-(2,4-diaminopteridine-6,7-diyl)diphenol, a PI3K inhibitor with potent activity against vascular leakage. Proceedings of MedChem Europe (Molecules that matter: case studies in medicinal chemistry); Berlin, April, 13–14, 2005.

  121. Shimada, M. et al. Preparation of fused azole-pyrimidine derivatives as PI3K inhibitors with therapeutic uses. PCT Int. Appl., WO-04029055 (2004).

  122. Kuang, R-R., Qian, F., Li, Z. & Wei, D-Z. Study on improving the selectivity of compounds that inhibit two PI3Ks (γ and δ). J. Mol. Model. 12, 445–452 (2006).

    Article  CAS  PubMed  Google Scholar 

  123. Kuang, R.-R., Qian, F., Li, Z., Wei, D.-Z. & Tang, Y. Action mechanisms and structure-activity relationships of PI3Kγ inhibitors on the enzyme: a molecular modeling study. Eur. J. Med. Chem. 41, 558–565 (2006).

    Article  CAS  PubMed  Google Scholar 

  124. Knight, Z. A. & Shokat, K. M. Features of selective kinase inhibitors. Chem. Biol. 12, 621–637 (2005). Excellent study offering new insights in the differential binding modes of various PI3K inhibitors.

    Article  CAS  PubMed  Google Scholar 

  125. Pope, R. M. Apoptosis as a therapeutic tool in rheumatoid arthritis. Nature Rev. Immunol. 2, 527–535 (2002).

    Article  CAS  Google Scholar 

  126. Ali, K. et al. Essential role for the p110δ phosphoinositide 3-kinase in the allergic response. Nature 431, 1007–1011 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. Yum, H. K. et al. Involvement of phosphoinositide 3-kinases in neutrophil activation and the development of acute lung injury. J. Immunol. 167, 6601–6608 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Alloatti, G. et al. Phosphoinositide 3-kinase γ-deficient hearts are protected from the PAF-dependent depression of cardiac contractility. Cardiovasc. Res. 60, 242–249 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Alloatti, G. et al. Phosphoinositide 3-kinase γ controls autonomic regulation of the mouse heart through Gi-independent downregulation of cAMP level. FEBS Lett. 579, 133–140 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Zhao, M. et al. Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-γ and PTEN. Nature 442, 457–460 (2006).

    Article  CAS  PubMed  Google Scholar 

  131. Gammill, R. B., Judge, T. M. & Morris, J. Preparation of antiatherosclerotic and antithrombotic 1-benzopyran-4-ones and 2-amino-1,3-benzoxazine-4-ones. PCT Int. Appl., WO-9119707 (1991).

  132. Hayakawa, M. et al. Preparation of condensed heteroaryl derivatives as phosphatidylinositol 3-kinase inhibitors and anticancer agents. PCT Int. Appl., WO-01083456 (2001).

  133. Hayakawa, M. et al. Preparation of imidazopyridine derivatives as phosphatidylinositol 3-kinase inhibitors and anticancer agents. PCT Int. Appl., WO-01083481 (2001).

  134. Melese, T., Perkins, E. L., Nguyen, A. T. Q. & Sun, D. Quinolin-2-ones and isoxazolo[3,4-c]quinolin-2-ones as modulators of phosphoinositide 3-kinase. PCT Int. Appl., WO-03035618 (2003).

  135. Melese, T., Perkins, E. L., Nguyen, A. T. Q. & Sun, D. Cyclohexothienopyrimidotriazoles and tetrahydropyranothienopyrimidotriazoles as modulators of phosphoinositide 3-kinase. PCT Int. Appl., WO-03034997 (2003).

  136. Chang, J., Xie, W. & Wang, L. Preparation of naphthoquinone derivatives as PI3 kinase inhibitors for treatment of cancer. Faming Zhuanli Shenqing Gongkai Shuomingshu, CN 1587255 (2004).

    Google Scholar 

  137. Garlich, J. R., Durden, D. L., Patterson, M., Su, J. & Suhr, R. G. Preparation of quaternized derivatives of (morpholinyl)phenylbenzopyranone as PI-3 kinase inhibitor prodrugs. PCT Int. Appl., WO-04089925 (2004).

  138. Nuss, J. M., Pecchi, S. & Renhowe, P. A. Preparation of 2,4,6-trisubstituted pyrimidines as phosphatidylinositol (pi) 3-kinase inhibitors and their use in the treatment of cancer. PCT Int. Appl., WO-04048365 (2004).

  139. Drees, B. E. et al. 2-Thioxo-oxazolidine inhibitors of phosphatidylinositol 3-kinase and their use in treatment of cancer, inflammation, and immune diseases. PCT Int. Appl., WO-05002514 (2005).

  140. Drees, B. E. et al. Preparation of pyrazoloquinolines and related derivatives as inhibitors of phosphatidylinositol 3-kinase. PCT Int. Appl., WO-05016245 (2005).

  141. Kawashima, S. et al. Preparation of 2-benzimidazolyl-4,6-dimorpholinylpyrimidine and 2-benzimidazolyl-4,6-dimorpholinyltriazine derivatives as antitumor agents. PCT Int. Appl., WO-05095389 (2005).

  142. Bailey, J. P., Giles, M. B. & Pass, M. Preparation of 2,4,6-trisubstituted pyrimidines as phosphatidylinositol 3 kinase inhibitors for treatment of cancer. PCT Int. Appl., WO-06005914 (2006).

  143. Pass, M. Preparation of 2,4,6-trisubstituted pyrimidines as phosphatidylinositol 3-kinase inhibitors and their use in the treatment of cancer. PCT Int. Appl., WO-06005915 (2006).

  144. Pass, M. Preparation of 2,4,6-trisubstituted pyrimidines as phosphatidylinositol 3-kinase (PI3 kinase) inhibitors and their use in the treatment of cancer. PCT Int. Appl., WO-06005918 (2006).

  145. Betzemeier, B. et al. Preparation of thiazoloindazoles for treatment and prevention of cancer. PCT Int. Appl., WO-06040281 (2006).

  146. Zask, A. et al. Analogs of 17-hydroxywortmannin as PI3K inhibitors. PCT Int. Appl., WO-06044453 (2006).

  147. Shuttleworth, S. J. et al. Pharmaceutical compounds as PI3K inhibitors. PCT Int. Appl., WO-06046040 (2006).

  148. Shuttleworth, S. J. et al. Pharmaceutical compounds as PI3K inhibitors. PCT Int. Appl., WO-06046031 (2006).

  149. Bengtsson, M. et al. 5-heteroaryl thiazoles and their use as PI3K inhibitors. PCT Int. Appl., WO-06051270 (2006).

  150. Andersen, R. et al. Meroterpenoid inhibitors of phosphoinositide 3 kinase (PI3K). PCT Int. Appl., WO-06081659 (2006).

  151. Marion, F. et al. Liphagal, a selective inhibitor of PI3 kinase α isolated from the sponge Aka coralliphaga: structure elucidation and biomimetic synthesis. Org. Lett. 8, 321–324 (2006).

    Article  CAS  PubMed  Google Scholar 

  152. Robertson, A. D. et al. Preparation and formulation of morpholino-substituted heterocycles as phosphoinositide 3-kinase inhibitors for therapeutic use. PCT Int. Appl., WO-01053266 (2001).

  153. Jackson, S. P. et al. Preparation of morpholinyl- and pyridinyl-substituted heterobicyclic ketones as selective inhibitors of phosphoinositide 3-kinase β for use against thrombosis. PCT Int. Appl., WO-04016607 (2004).

  154. Sadhu, C. et al. Quinazolinone derivatives as inhibitors of human phosphatidylinositol 3-kinase δ. PCT Int. Appl., WO-01081346 (2001).

  155. Sadhu, C. et al. Preparation of purinylquinazolinones as inhibitors of human phosphatidylinositol 3-kinase δ. PCT Int. Appl., WO-03035075 (2003).

  156. Shuttleworth, S. J. et al. Pharmaceutical compounds as PI3K inhibitors. PCT Int. Appl., WO-06046035 (2006).

  157. Gogliotti, R. D., Lee, H. T., Sexton, K. E. & Visnick, M. 3-arylsulfanyl and 3-heteroarylsulfanyl substituted benzo[b]thiophenes as therapeutic agents. PCT Int. Appl., WO-04108716 (2004).

  158. Gogliotti, R. D., Lee, H. T., Sexton, K. E. & Visnick, M. A preparation of (cycloalkylsulfanyl)benzo[b]thiophene derivatives, useful as selective PI3Kγ inhibitors. PCT Int. Appl., WO-04108714 (2004).

  159. Rueckle, T., Shaw, J., Church, D. D. & Covini, D. Preparation of 2-imino-4-(thio)oxo-5-polycyclovinylazolines as PI3 kinase inhibitors. WO-05011686 (2005).

  160. Rueckle, T. et al. Pyridine methylene azolidinones and use thereof phosphoinositide inhibitors. PCT Int. Appl., WO-06024666 (2006).

Download references

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.

Author information

Authors and Affiliations

  1. Serono Pharmaceutical Research Institute, Serono International S.A., 14 Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland

    Thomas Rückle, Matthias K. Schwarz & Christian Rommel

Authors
  1. Thomas Rückle
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Matthias K. Schwarz
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Christian Rommel
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding authors

Correspondence to Matthias K. Schwarz or Christian Rommel.

Ethics declarations

Competing interests

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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2145

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing