6xrm | pdb_00006xrm
Crystal structure of human PI3K-gamma in complex with Compound 4
Structural highlights
Function[PK3CG_HUMAN] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(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. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to ADRBK1 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe selective inhibition of the lipid signaling enzyme PI3Kgamma constitutes an opportunity to mediate immunosuppression and inflammation within the tumor microenvironment but is difficult to achieve due to the high sequence homology across the class 1 PI3K isoforms. Here, we describe the design of a novel series of potent PI3Kgamma inhibitors that attain high isoform selectivity through the divergent projection of substituents into both the 'selectivity' and 'alkyl-induced' pockets within the ATP binding site of PI3Kgamma. These efforts have culminated in the discovery of 5-[2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-[(1S)-1-c yclopropylethyl]-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (4, IC50 = 0.064 microM, THP-1 cells), which displays >700-fold selectivity for PI3Kgamma over the other class I isoforms and is a promising step towards the identification of a clinical development candidate. The structure-activity relationships identified throughout this campaign demonstrate that greater gamma-selectivity can be achieved by inhibitors that occupy an 'alkyl-induced' pocket and possess bicyclic hinge-binding motifs capable of forming more than one hydrogen bond to the hinge region of PI3Kgamma. Discovery of Potent and Selective PI3Kgamma Inhibitors.,Drew SL, Thomas-Tran R, Beatty JW, Fournier J, Lawson KV, Miles DH, Mata G, Sharif EU, Yan X, Mailyan AK, Ginn E, Chen J, Wong K, Soni D, Dhanota P, Chen PY, Shaqfeh SG, Meleza C, Pham AT, Chen A, Zhao X, Banuelos J, Jin L, Schindler U, Walters MJ, Young SW, Walker NP, Leleti MR, Powers JP, Jeffrey JL J Med Chem. 2020 Aug 31. doi: 10.1021/acs.jmedchem.0c01203. PMID:32865410[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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