| Structural highlights
Function
[PK3CD_MOUSE] Phosphoinositide-3-kinase (PI3K) that phosphorylates PftdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T-helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Have a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Have important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kgamma inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as 15, which is a potent and remarkably selective PI3Kgamma inhibitor with ADME properties suitable for oral administration. Compound 15 was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally.
Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-gamma Inhibitors.,Pemberton N, Mogemark M, Arlbrandt S, Bold P, Cox RJ, Gardelli C, Holden NS, Karabelas K, Karlsson J, Lever S, Li X, Lindmark H, Norberg M, Perry MWD, Petersen J, Rodrigo Blomqvist S, Thomas M, Tyrchan C, Westin Eriksson A, Zlatoidsky P, Oster L J Med Chem. 2018 Jun 18. doi: 10.1021/acs.jmedchem.8b00447. PMID:29852070[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek SE, Salpekar A, Waterfield MD, Smith AJ, Vanhaesebroeck B. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science. 2002 Aug 9;297(5583):1031-4. Epub 2002 Jul 18. PMID:12130661 doi:http://dx.doi.org/10.1126/science.1073560
- ↑ Clayton E, Bardi G, Bell SE, Chantry D, Downes CP, Gray A, Humphries LA, Rawlings D, Reynolds H, Vigorito E, Turner M. A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation. J Exp Med. 2002 Sep 16;196(6):753-63. PMID:12235209
- ↑ Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C, Kuehn N, Gray A, Giddings J, Peskett E, Fox R, Bruce I, Walker C, Sawyer C, Okkenhaug K, Finan P, Vanhaesebroeck B. Essential role for the p110delta phosphoinositide 3-kinase in the allergic response. Nature. 2004 Oct 21;431(7011):1007-11. PMID:15496927 doi:http://dx.doi.org/10.1038/nature02991
- ↑ Webb LM, Vigorito E, Wymann MP, Hirsch E, Turner M. Cutting edge: T cell development requires the combined activities of the p110gamma and p110delta catalytic isoforms of phosphatidylinositol 3-kinase. J Immunol. 2005 Sep 1;175(5):2783-7. PMID:16116162
- ↑ Jarmin SJ, David R, Ma L, Chai JG, Dewchand H, Takesono A, Ridley AJ, Okkenhaug K, Marelli-Berg FM. T cell receptor-induced phosphoinositide-3-kinase p110delta activity is required for T cell localization to antigenic tissue in mice. J Clin Invest. 2008 Mar;118(3):1154-64. doi: 10.1172/JCI33267. PMID:18259608 doi:http://dx.doi.org/10.1172/JCI33267
- ↑ Guo H, Samarakoon A, Vanhaesebroeck B, Malarkannan S. The p110 delta of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation. J Exp Med. 2008 Sep 29;205(10):2419-35. doi: 10.1084/jem.20072327. Epub 2008 Sep , 22. PMID:18809712 doi:http://dx.doi.org/10.1084/jem.20072327
- ↑ Saudemont A, Garcon F, Yadi H, Roche-Molina M, Kim N, Segonds-Pichon A, Martin-Fontecha A, Okkenhaug K, Colucci F. p110gamma and p110delta isoforms of phosphoinositide 3-kinase differentially regulate natural killer cell migration in health and disease. Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5795-800. doi:, 10.1073/pnas.0808594106. Epub 2009 Mar 18. PMID:19297623 doi:http://dx.doi.org/10.1073/pnas.0808594106
- ↑ Pemberton N, Mogemark M, Arlbrandt S, Bold P, Cox RJ, Gardelli C, Holden NS, Karabelas K, Karlsson J, Lever S, Li X, Lindmark H, Norberg M, Perry MWD, Petersen J, Rodrigo Blomqvist S, Thomas M, Tyrchan C, Westin Eriksson A, Zlatoidsky P, Oster L. Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-gamma Inhibitors. J Med Chem. 2018 Jun 18. doi: 10.1021/acs.jmedchem.8b00447. PMID:29852070 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00447
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