4bfr | pdb_00004bfr

Discovery and Optimization of Pyrimidone Indoline Amide PI3Kbeta Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers

spinqualitylabelsall models 4bfr, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4bfr is a 2 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: J82 Activity: Phosphatidylinositol-4,5-bisphosphate 3-kinase, with EC number 2.7.1.153 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [PK3CB_MOUSE] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and 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. Involved in the activation of AKT1 upon stimulation by G-protein coupled receptors (GPCRs) ligands such as CXCL12, sphingosine 1-phosphate, and lysophosphatidic acid. May also act downstream receptor tyrosine kinases. Required in different signaling pathways for stable platelet adhesion and aggregation. Plays a role in platelet activation signaling triggered by GPCRs, alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) and ITAM (immunoreceptor tyrosine-based activation motif)-bearing receptors such as GP6. Regulates the strength of adhesion of ITGA2B/ ITGB3 activated receptors necessary for the cellular transmission of contractile forces. Required for platelet aggregation induced by F2 (thrombin) and thromboxane A2 (TXA2). Has a role in cell survival. May have a role in cell migration. Involved in the early stage of autophagosome formation. Modulates the intracellular level of PtdIns3P (Phosphatidylinositol 3-phosphate) and activates PIK3C3 kinase activity. May act as a scaffold, independently of its lipid kinase activity to positively regulate autophagy. May have a role in insulin signaling as scaffolding protein in which the lipid kinase activity is not required. May have a kinase-independent function in regulating cell proliferation and in clathrin-mediated endocytosis. Mediator of oncogenic signal in cell lines lacking PTEN. The lipid kinase activity is necessary for its role in oncogenic transformation. Required for the growth of ERBB2 and RAS driven tumors. Publication Abstract from PubMed Compelling molecular biology publications have reported the implication of phosphoinositide kinase PI3K in PTEN-deficient cell lines growth and proliferation. These findings supported a scientific rationale for the development of PI3K-specific inhibitors for the treatment of PTEN-deficient cancers. This paper describes the discovery of 2-[2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one 7 and the optimization of this new series of active and selective pyrimidone indoline amide PI3K inhibitors. 2-[2-(2-Methyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin -4-one 28, identified following a carefully designed methyl scan, displayed improved physicochemical and in vitro pharmacokinetic properties. Structural biology efforts enabled the obtention of the first X-Ray co-crystal structure of p110 with the selective inhibitor compound 28 bound to the ATP site. The non-planar binding mode described herein is consistent with observed SAR for the series. Compound 28 demonstrated significant in vivo activity in a UACC-62 xenograft model in mice, warranting further preclinical investigation. Following successful development, compound 28 entered phase I/Ib clinical trial in patients with advanced cancer. Discovery and Optimization of Pyrimidone Indoline Amide PI3Kss Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers.,Certal V, Carry JC, Halley F, Virone-Oddos A, Thompson F, Filoche-Romme B, El-Ahmad Y, Karlsson A, Charrier V, Delorme C, Rak A, Abecassis PY, Amara C, Vincent L, Bonnevaux H, Nicolas JP, Mathieu M, Bertrand T, Marquette JP, Michot N, Benard T, Perrin MA, Lemaitre O, Guerif S, Perron S, Monget S, Gruss-Leleu F, Doerflinger G, Guizani H, Brollo M, Delbarre L, Bertin L, Richepin P, Loyau V, Garcia-Echeverria C, Lengauer C, Schio L J Med Chem. 2014 Jan 4. PMID:24387221 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphoinositide 3-Kinases

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