6tns | pdb_00006tns
PI3K delta in complex with 2methoxyN[2methoxy5(7{[(2R)4(oxetan3 yl)morpholin2yl]methoxy}1,3dihydro2 benzofuran5yl)pyridin3yl]ethane1 sulfonamide
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 PubMedOptimisation of a lead series of PI3Kdelta inhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for the class III PI3K, Vps34, as for PI3Kdelta and compound 19 was not well-tolerated in a 7 day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kdelta over Vps34 and a focus on oral PK properties resulted in the discovery of compound 41, which showed improved toxicological outcomes at similar exposures to compound 19. Optimization of Orally Bioavailable PI3Kdelta Inhibitors and Identification of Vps34 as a key off-target activity.,Henley ZA, Amour A, Barton N, Bantscheff M, Bergamini G, Bertrand SM, Convery MA, Down KD, Duempelfeld B, Edwards CD, Grandi P, Gore PM, Keeling S, Livia S, Mallett DN, Maxwell AC, Price M, Rau C, Reinhard F, Rowedder JE, Rowland P, Taylor J, Thomas D, Hessel EM, Hamblin N J Med Chem. 2019 Dec 19. doi: 10.1021/acs.jmedchem.9b01585. PMID:31855425[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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