7oi4
mPI3Kd in complex with compound 12mPI3Kd in complex with compound 12
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 PubMedStarting from our previously described PI3Kgamma inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kgammadelta inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets. Discovery of AZD8154, a Dual PI3Kgammadelta Inhibitor for the Treatment of Asthma.,Perry MWD, Bjorhall K, Bold P, Brulls M, Borjesson U, Carlsson J, Chang HA, Chen Y, Eriksson A, Fihn BM, Fransson R, Fredlund L, Ge H, Huang H, Karabelas K, Lamm Bergstrom E, Lever S, Lindmark H, Mogemark M, Nikitidis A, Palmgren AP, Pemberton N, Petersen J, Rodrigo Blomqvist M, Smith RW, Thomas MJ, Ullah V, Tyrchan C, Wennberg T, Westin Eriksson A, Yang W, Zhao S, Oster L J Med Chem. 2021 Jun 24;64(12):8053-8075. doi: 10.1021/acs.jmedchem.1c00434. Epub, 2021 Jun 3. PMID:34080862[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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