| Structural highlights
Disease
[PK3CD_HUMAN] Activated PIK3-delta syndrome. The disease is caused by mutations affecting the gene represented in this entry.
Function
[PK3CD_HUMAN] 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. Isoform 2 may be involved in stabilizing total RAS levels, resulting in increased ERK phosphorylation and increased PI3K activity.[1] [2] [P85A_BOVIN] Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling (By similarity).
Publication Abstract from PubMed
Inhibitors of the class I phosphoinositide 3-kinase (PI3K) isoform PI3Kalpha have received substantial attention for their potential use in cancer therapy. Despite the particular attraction of targeting PI3Kalpha, achieving selectivity for the inhibition of this isoform has proved challenging. Herein we report the discovery of inhibitors of PI3Kalpha that have selectivity over the other class I isoforms and all other kinases tested. In GDC-0032 (3, taselisib), we previously minimized inhibition of PI3Kbeta relative to the other class I insoforms. Subsequently, we extended our efforts to identify PI3Kalpha-specific inhibitors using PI3Kalpha crystal structures to inform the design of benzoxazepin inhibitors with selectivity for PI3Kalpha through interactions with a nonconserved residue. Several molecules selective for PI3Kalpha relative to the other class I isoforms, as well as other kinases, were identified. Optimization of properties related to drug metabolism then culminated in the identification of the clinical candidate GDC-0326 (4).
The Rational Design of Selective Benzoxazepin Inhibitors of the alpha-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2-((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1 ,4]oxazepin-9-yl)oxy)propanamide (GDC-0326).,Heffron TP, Heald RA, Ndubaku C, Wei B, Augistin M, Do S, Edgar K, Eigenbrot C, Friedman L, Gancia E, Jackson PS, Jones G, Kolesnikov A, Lee LB, Lesnick JD, Lewis C, McLean N, Mortl M, Nonomiya J, Pang J, Price S, Prior WW, Salphati L, Sideris S, Staben ST, Steinbacher S, Tsui V, Wallin J, Sampath D, Olivero AG J Med Chem. 2016 Jan 20. PMID:26741947[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Soond DR, Bjorgo E, Moltu K, Dale VQ, Patton DT, Torgersen KM, Galleway F, Twomey B, Clark J, Gaston JS, Tasken K, Bunyard P, Okkenhaug K. PI3K p110delta regulates T-cell cytokine production during primary and secondary immune responses in mice and humans. Blood. 2010 Mar 18;115(11):2203-13. doi: 10.1182/blood-2009-07-232330. Epub 2010 , Jan 15. PMID:20081091 doi:http://dx.doi.org/10.1182/blood-2009-07-232330
- ↑ Fransson S, Uv A, Eriksson H, Andersson MK, Wettergren Y, Bergo M, Ejeskar K. p37delta is a new isoform of PI3K p110delta that increases cell proliferation and is overexpressed in tumors. Oncogene. 2012 Jul 5;31(27):3277-86. doi: 10.1038/onc.2011.492. Epub 2011 Oct 24. PMID:22020336 doi:http://dx.doi.org/10.1038/onc.2011.492
- ↑ Heffron TP, Heald RA, Ndubaku C, Wei B, Augistin M, Do S, Edgar K, Eigenbrot C, Friedman L, Gancia E, Jackson PS, Jones G, Kolesnikov A, Lee LB, Lesnick JD, Lewis C, McLean N, Mortl M, Nonomiya J, Pang J, Price S, Prior WW, Salphati L, Sideris S, Staben ST, Steinbacher S, Tsui V, Wallin J, Sampath D, Olivero AG. The Rational Design of Selective Benzoxazepin Inhibitors of the alpha-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2-((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1 ,4]oxazepin-9-yl)oxy)propanamide (GDC-0326). J Med Chem. 2016 Jan 20. PMID:26741947 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01483
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