Early research indicated that PI3Kγ is crucial for leukocyte migration and that loss of PI3Kγ is protective in a wide variety of inflammatory disease models (Hirsch et al., Science 2000). These contributions demonstrated that PI3Kγ is a key mediator of leukocyte migration, critical in various inflammatory conditions as well as in the heart (Patrucco et al., Cell 2004; Vecchione et al., 2005; Damilano et al., 2011).

  • Hirsch E, Katanaev VL, Garlanda C, Azzolino O, Pirola L, Silengo L, Sozzani S, Mantovani A, Altruda F, Wymann MP. Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. Science. 2000 Feb 11;287(5455):1049-53.
  • Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A, Brancaccio M, Marengo S, Russo G, Azzolino O, Rybalkin SD, Silengo L, Altruda F, Wetzker R, Wymann MP, Lembo G, Hirsch E. PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell. 2004 Aug 6;118(3):375-87.
  • Vecchione C, Patrucco E, Marino G, Barberis L, Poulet R, Aretini A, Maffei A, Gentile MT, Storto M, Azzolino O, Brancaccio M, Colussi GL, Bettarini U, Altruda F, Silengo L, Tarone G, Wymann MP, Hirsch E, Lembo G. Protection from angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3Kgamma. J Exp Med. 2005 Apr 18;201(8):1217-28.
  • Damilano F, Franco I, Perrino C, Schaefer K, Azzolino O, Carnevale D, Cifelli G, Carullo P, Ragona R, Ghigo A, Perino A, Lembo G, Hirsch E. Distinct effects of leukocyte and cardiac phosphoinositide 3-kinase γ activity in pressure overload-induced cardiac failure. Circulation. 2011 Feb 1;123(4):391-9.

The key finding that PI3K are both enzymes and scaffold proteins (Patrucco et al., Cell 2004) led to the identification of the role of PI3Kγ in scaffolding PKA and acting at the crossroads between cAMP and PtdIns(3,4,5)P3 pathways (Perino et al., Mol Cell 2011).

  • Perino A, Ghigo A, Ferrero E, Morello F, Santulli G, Baillie GS, Damilano F, Dunlop AJ, Pawson C, Walser R, Levi R, Altruda F, Silengo L, Langeberg LK, Neubauer G, Heymans S, Lembo G, Wymann MP, Wetzker R, Houslay MD, Iaccarino G, Scott JD, Hirsch E. Integrating cardiac PIP3 and cAMP signaling through a PKA anchoring function of p110γ. Mol Cell. 2011 Apr 8;42(1):84-95.

The development of a pan-PI3K inhibitor for the treatment of inflammatory respiratory diseases (Pirali T Chem Med Chem. 2017), enabled to efficiently treat severe asthma and Idiopathic Pulmonary Fibrosis (Campa et al., Nature Comm.).

  • Pirali T, Ciraolo E, Aprile S, Massarotti A, Berndt A, Griglio A, Serafini M, Mercalli V, Landoni C, Campa CC, Margaria JP, Silva RL, Grosa G, Sorba G, Williams R, Hirsch E, Tron GC.Identification of a Potent Phosphoinositide 3-Kinase Pan Inhibitor Displaying a Strategic Carboxylic Acid Group and Development of Its Prodrugs. Chem Med Chem. 2017 Sep 21;12(18):1542-1554.
  • Carlo C. Campa, Rangel L. Silva, Jean P. Margaria, Tracey Pirali, Matheus S. Mattos, Lucas R. Kraemer, Diego C. Reis, Giorgio Grosa, Francesca Copperi, Eduardo M. Dalmarco, Roberto C.P. Lima-Júnior, Silvio Aprile, Valentina Sala, Federica Dal Bello, Douglas Prado, Jose Carlos Alves-Filho, Claudio Medana, Giovanni D. Cassali, Gian Cesare Tron, Mauro M. Teixeira, Elisa Ciraolo, Remo C. Russo, Emilio Hirsch. Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis. Nat Comm.