8bcy
From Proteopedia
HUMAN PI3KDELTA IN COMPLEX WITH COMPOUND 13
Structural highlights
DiseasePK3CD_HUMAN Activated PIK3-delta syndrome. The disease is caused by mutations affecting the gene represented in this entry. FunctionPK3CD_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] Publication Abstract from PubMedPI3Kdelta is a lipid kinase which plays a key role in airway inflammatory conditions. Accordingly, the inhibition of PI3Kdelta can be considered a valuable strategy for the treatment of chronic respiratory diseases such as Asthma and Chronic obstructive pulmonary disease (COPD). In this work, we describe our efforts to identify new PI3Kdelta inhibitors following an "inhalation by design" strategy. Starting from the identification of a purine scaffold, we carried out a preliminary SAR expansion which led to the identification of a new hit characterized by a high enzymatic potency and moderate PI3Kdelta selectivity. A subsequent optimization led to novel purine based derivatives with favorable in vitro ADME profiles, which might represent promising starting points for future development of new inhaled drug candidates. Application of an "inhalation by design" approach to the identification and in-vitro evaluation of novel purine based PI3Kdelta inhibitors.,Mazzucato R, Roberti M, Capelli AM, Rancati F, Biagetti M, Fiorelli C, Bruno P, Ronchi P, Bertolini S, Corsi M, Pala D Eur J Med Chem. 2023 Jun 5;254:115331. doi: 10.1016/j.ejmech.2023.115331. Epub , 2023 Apr 7. PMID:37094451[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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