9gdi
From Proteopedia
HUMAN PI3KDELTA IN COMPLEX WITH ISOCUMARIN INHIBITOR 10
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 PubMedThe design of inhaled selective phosphatidylinositol 3-kinase delta (PI3Kdelta) inhibitors for the treatment of inflammatory lung diseases was pursued. Knowledge-based design of a novel isocoumarin scaffold that was able to adopt a propeller-shape topology ensured the desired PI3Kdelta selectivity. Achievement of low nanomolar cellular potencies through hinge binder group optimization, reduction of intrinsic permeability through head group optimization to extend lung retention, and screening of crystalline forms suitable for administration as dry powders culminated in the identification of compound 18. This novel inhaled selective PI3Kdelta inhibitor displayed durable anti-inflammatory activity in a disease-relevant rat model of Th-2-driven acute lung inflammation and safe in vitro and in vivo preclinical profiles. Therefore, compound 18 showed the appropriate discovery profile and was progressed to clinical trials in healthy volunteers and chronic obstructive pulmonary disease (COPD) patients as CHF-6523. Discovery of CHF-6523, an Inhaled Selective PI3Kdelta Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease.,Bruno P, Pala D, Micoli A, Corsi M, Accetta A, Carzaniga L, Ronchi P, Fiorelli C, Formica M, Pizzirani D, Mazzucato R, Guariento S, Bertolini S, Martucci C, Allen AD, Mileo V, Capacchi S, Gallo PM, Fioni A, Xanxo Fernandez S, Villetti G, Puccini P, Civelli M, Guala M, Retini M, Martinelli P, Visentini F, Pavoni V, Daldosso M, Fontana S, Biagetti M, Capelli AM J Med Chem. 2024 Dec 5. doi: 10.1021/acs.jmedchem.4c02062. PMID:39635891[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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