5t2g
mPI3Kd IN COMPLEX WITH 7i
Structural highlights
FunctionPK3CD_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 PubMedA novel class of potent PI3Kdelta inhibitors with >1000-fold selectivity against other class I PI3K isoforms is described. Optimization of the substituents on a triazole aminopyrazine scaffold, emerging from an in-house PI3Kalpha program, turned moderately selective PI3Kdelta compounds into highly potent and selective PI3Kdelta inhibitors. These efforts resulted in a series of aminopyrazines with PI3Kdelta IC501nM in the enzyme assay, some of the most selective PI3Kdelta inhibitors published to date, with a cell potency in a JeKo-cell assay of 20-120nM. Discovery of triazole aminopyrazines as a highly potent and selective series of PI3Kdelta inhibitors.,Terstiege I, Perry M, Petersen J, Tyrchan C, Svensson T, Lindmark H, Oster L Bioorg Med Chem Lett. 2017 Feb 1;27(3):679-687. doi: 10.1016/j.bmcl.2016.11.004. , Epub 2016 Nov 2. PMID:28017532[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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